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Background and Aims It is estimated that Chronic Kidney Disease (CKD) accounts for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Although traditional CV risk factors are prevalent, other non-traditional CV risk factors such as vascular calcification (VC) are believed to contribute to this disproportionate CV risk burden in CKD subjects. We sought to investigate the association of Coronary Artery Calcification (CAC) progression with all-cause mortality in a cohort of patients new to hemodialysis (HD). Method This is a post hoc analysis of the Independent study (NCT00710788) originally designed to test the impact of 2 different phosphate binder regimens on various hard as well as surrogate endpoint in HD subjects. A total of 412 (88.4% of the Independent study cohort) underwent repeated CAC quantification according to the Agatston methods at study inception as well as after 12 months of follow-up. The square root method was used to assess CAC progression (CACP) and survival analyses were used to check the association of CACP and all-cause mortality. Results 412 middle age (65 years) men and women (51.2%) were considered. Detectable CAC was present in about 2 out 3 patients (68.2%) at study inception. At 12 months of follow-up completion, about 1 out of 3 subjects (33.1%) experience a significant CACP. CACP was associated with older age and use of calcium-based phosphate binders. At study completion (median follow-up: 36 months) 106 patients expired of all-cause. Age, diabetes mellitus, atherosclerotic CV events, baseline CAC extension were predictors of unfavorable outcome. Multivariable adjusted analysis confirmed an independent association of both baseline CAC (Hazard Ratio 1.29; 95% Confidence Interval: 1.17-1.44) and CACP (HR: 5.16; 95%CI: 2.61-10.21) with all-cause mortality. However, CACP diminished the risk associated with baseline CAC (p for interaction term 0.002) and use of calcium-free phosphate binders significantly weakened the link between CACP (HR. 1.95; 95%CI: 0.92-4.16) and mortality Conclusion Baseline CAC as well as CACP predict mortality in incident to HD individuals. Nevertheless, CACP mitigates the risk associated with baseline CAC and calcium-free phosphate binders attenuates the association of CACP and mortality, suggesting that CACP modulation may impact survival in this population

Background: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. Methods: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). Results: We studied 562 patients (age 66.2 ± 14.5 y, 61% males, eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was “absent” in 50.7%, “resolving” in 15.6%, “new onset” in 16.6%, and “persistent” in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p &lt, 0.0001), K-binders (from 2.0 to 7.7%, p &lt, 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p &lt, 0.001), these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR &lt, 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). Conclusions: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

Nephrology in Italy was organized as a medical society in 1957. A publicly funded system provides no-fee and universal healthcare for all people within the national territory, including renal replacement therapy, with coverage of renal dialysis and kidney transplantation. With a population of 60 million, about 46,474 patients are currently on dialysis. Hemodialysis is the main modality of renal replacement therapy, treating 90% of the patients on chronic dialysis. Peritoneal dialysis is still underutilized. Similarly, transplantation, with about 2200 kidney transplants per year, can be expanded. This chapter presents a general overview of nephrology in Italy, covering historical aspects, the main renal diseases, and renal replacement therapy, including hemodialysis, peritoneal dialysis, and kidney transplantation.

BackgroundConcerns about adherence and quality of life (QoL) limit the diffusion of low-protein diets (LPDs) as a way to slow chronic kidney disease (CKD) progression and postpone dialysis. The aim of this multicentre study is to assess dietary satisfaction in stable CKD patients.MethodsThis was a multicentre cross-sectional study with long-term follow-up data. Prevalent patients on LPD for at least 6 months were selected in four Italian centres. QoL was assessed using the World Health Organization Quality of Life questionnaire, and diet satisfaction with the Modification of Diet in Renal Disease satisfaction questionnaire. Comorbidity was assessed by Charlson Comorbidity Index, estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation and protein intake by Maroni–Mitch formula. Survival was analysed with Kaplan–Meier curves and Cox Proportional Hazard Model.ResultsFour hundred and twenty-two CKD Stages 3–5 patients were enrolled. Over 95% were on moderately restricted diets (0.6 g/kg/day). Compliance was good (protein intake: 0.59 g/kg/day at baseline, 0.72 at the end of follow-up). Median dietary satisfaction was 4 on a 1–5 scale. QoL was not affected by the type of diet, but was influenced by age, comorbidity and setting of care. Two years later, at the end of follow-up, 66.6% of the patients were still on a diet; the main causes of discontinuation were dialysis and death. The dropout rate was low (5.5%); in Cox analysis, patient and renal survival were influenced by age and eGFR, but not by QoL, setting of care or type of diet.ConclusionsLPDs are compatible with high dietary satisfaction and minimal dropout, at least in patients who are able to follow such a diet for at least 6 months.

In chronic kidney disease (CKD), the progressive decline in the renal excretory function leads to accumulation of urea and toxins in the blood. The CKD-associated dysbiosis of gut microbiota further contributes to uremia by increasing intestinal toxins production. Gut microbiota is involved in a complex network of human organs, mediated by microbial metabolites: in CKD, gut-heart and gut-brain axes may have a role in increased cardiovascular risk and neuropsychiatric disorders. While the cardiovascular toxicity of some microbial molecules is well known, their presumptive neurotoxicity needs to be confirmed by specific studies. In this review, we describe gut-heart and gut-brain axes in CKD, with an overview of the experimental and human studies characterizing CKD-associated gut microbiota, and we discuss the benefits coming from new approaches aimed at gut manipulation. Microbiota metabolism is emerging as a modifiable non-traditional risk factor in nephrology. In order to take advantage of this issue, it is necessary to consider the microbiota manipulation as part of the nutritional management of CKD. Integrating the low-protein nutritional approach with prebiotic, probiotic and synbiotic supplementation is a promising tool to control disease progression and comorbidities, though an extensive validation in large-scale clinical trials is still required.

In recent years, novel anticoagulant drugs have been introduced in the clinical armamentarium and have progressively gained momentum. Although their use is increasing among CKD patients, some skepticism about their risk–benefit ratio still persists. We sought to investigate the safety and effectiveness of rivaroxaban in a cohort of moderate-to-advanced CKD patients. This observational, retrospective, longitudinal study involved 347 consecutive CKD stage 3b–4 (according to NKF–KDOQI guidelines) patients enrolled from 8 cardiac outpatient clinics between March 2015 and October 2017. All patients received anticoagulation (100 warfarin vs. 247 rivaroxaban) as part of their non-valvular atrial fibrillation management at the attending physician’s discretion. Clinical effectiveness (defined as the occurrence of ischemic stroke, venous thromboembolism, or transient ischemic attack) and safety (intracranial hemorrhage, gastrointestinal or other bleeding) were assessed separately. Over a mean follow-up period of 16 ± 0.3 months, 25 stroke episodes (15 hemorrhagic, and 10 ischemic) occurred in 24 warfarin treated patients vs. none in the rivaroxaban arm. There were 5 vs. 0 episodes of deep venous thrombosis and 8 vs. 2 major episodes of bleeding in the warfarin and rivaroxaban groups, respectively. In contrast, the proportion of minor episodes of bleeding was similar between groups. Rivaroxaban seems a safe and effective therapeutic option in CKD stage 3b–4 patients. However, future randomized controlled trials are needed to definitively establish the role of rivaroxaban in CKD patients.

Background Patients on standard dialysis, in particular those on high-flux and high-efficiency dialysis, are exposed to hundreds of liters of dialysis-water per week. The quality of dialysis-water is a factor responsible for inflammation in dialysis patients. Inflammation is a potent trigger of atherosclerosis and a pathogenetic factor in anemia, increasing mortality and morbidity in dialysis patients. Current systems for water treatment do not completely eliminate bacteria and endotoxins. This prospective study tested whether improved dialysis-water purity by an additional ultrafilter can reduce inflammation and ameliorate hemoglobin levels, with a consequent reduction in erythropoietin-stimulating agents (ESA). Methods An ultrafilter, composed of two serially positioned devices with polysulfone membranes of 2.0 and 1.0 m2, respectively, was positioned within the fluid pathway before the dialysis machine. Prevalent dialysis patients were assigned either to continue dialysis with conventional dialysis-water (control phase) or to initiate dialysis sessions with improved dialysis-water purity (study phase). After 6 months, patients were crossed over. Total study duration was 1 year. Routine chemistry, bacterial count, endotoxin levels in dialysis-water as well as blood levels of pro- and anti-inflammatory cytokines, human serum amyloid A, C-reactive protein and fraction 5 of complement were measured. Results Thirty-two patients completed the study. Mean bacterial count was lower and endotoxin levels were absent in dialysis-water obtained with the ultrafilter. At the end of the study-phase, C-reactive protein and pro-inflammatory cytokines decreased while anti-inflammatory ones increased. Hemoglobin levels were improved with lower ESA doses. Conclusions An additional ultrafilter improved dialysis-water purity, reduced levels of inflammation markers, ameliorated hemoglobin concentration with reduced ESA doses. These results remain speculative but they may generate studies to assess whether improved dialysis-water quality with an ultrafilter can reduce inflammation and improve survival of dialysis patients. Electronic supplementary material The online version of this article (doi:10.1007/s40620-017-0422-x) contains supplementary material, which is available to authorized users.

Background: The perturbation of phosphate homeostasis portends unfavorable outcomes in chronic kidney disease (CKD). However, the absence of randomized clinical trials (RCT) fuels the discussion of whether phosphate or some other phosphorous-related factor(s) such as fibroblast growth factor 23 (FGF-23) mediates the cardiovascular and systemic toxicity. We herein test whether the fractional excretion of phosphate (FeP) as a marker of renal stress to excrete phosphorous predicts unfavorable outcomes in CKD patients. Methods: Retrospective, cross-sectional observational study. For current analysis, an historical cohort of 407 records of CKD stage 3b-5 patients attending between January 2010 and October 2015 at the Nephrology Unit of Solofra (AV), Italy were utilized. Demographic, clinical, laboratory, and outcome data were identified through the subjects&rsquo, medical records. We tested whether quartiles of FeP are associated with the risk of CKD progression or all causes of death. Parametric as well as non-parametric tests, linear and logistic regression, as well as survival analysis were utilized. Results: Overall, we investigated middle-age (mean 66.0, standard deviation 12.3 years) men and women (male 43%) with CKD stage 3b to 5 (creatinine clearance 32.0 (13.3) mL/min). Older age, lower diastolic blood pressure, poor renal function, as well as higher serum phosphate were associated with FeP. Patients with higher FeP were at an increased risk of starting dialysis or dying (hazard ratio 2.40, 95% confidence interval (1.44, 3.99)). Notably, when the two endpoints were analyzed separately, FeP was associated with renal but not all-cause survival. Conclusion: FeP is associated with ESRD, but not all-cause mortality risk in a large cohort of moderate to advanced CKD patients. Future efforts are required to validate FeP as a marker of nephron stress and risk factor for CKD progression in this high-risk population.

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and/or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

Epicardial adipose tissue (EAT) is localized between the myocardial surface and visceral layer of the pericardium. It is a metabolically active organ that secretes several cytokines which modulate cardiovascular morphology and function. EAT may interact locally with coronary arteries through paracrine secretion mechanisms. Cytokines from peri-adventitial EAT may pass through the coronary wall by diffusion from the outside to the inside, interacting with cells. An additional potential mechanism by which EAT interacts locally with coronary arteries may be the vasocrine secretion.EAT may play a significant role as a modulator of cardiac functions. In physiologic conditions, EAT has biochemical cardio-protective properties, secreting anti-atherosclerosis substances; in metabolic disease states, EAT secretes bioactive molecules that may play an important role in the pathogenesis of coronary artery disease and cardiac arrhythmias by promoting atherosclerosis. EAT has been evaluated both in the general population and in metabolic disease states that are characterized by inflammation, such as cardiovascular diseases and chronic kidney disease.This review focuses on the current state of knowledge on EAT as a reliable new parameter for cardiovascular risk stratification in high risk populations.

CKD-related nutritional therapy (NT) is a crucial cornerstone of CKD patients' treatment, but the role of NT has not been clearly investigated in autosomal dominant polycystic kidney disease (ADPKD). Several clinical studies have focused on new pharmacological approaches to delay cystic disease progression, but there are no data on dietary interventions in ADPKD patients. The aim of this paper is to analyze the evidence from the literature on the impact of five nutritional aspects (water, sodium, phosphorus, protein intake, and net acid load) in CKD-related ADPKD extrapolating-where information is unavailable-from what occurs in CKD non-ADPKD patients Sodium intake restriction could be useful in decreasing the growth rate of cysts. Although further evidence is needed, restriction of phosphorus and protein intake restriction represent cornerstones of the dietary support of renal non-ADPKD patients and common sense can guide their use. It could be also helpful to limit animal protein, increasing fruit and vegetables intake together with a full correction of metabolic acidosis. Finally, fluid intake may be recommended in the early stages of the disease, although it is not to be prescribed in the presence of moderate to severe reduction of renal function.

Background Protein carbamylation is one of the non-enzymatic reactions involved in protein molecular ageing. We sought to investigate the relationship between urea levels and protein carbamylation, and whether a Mediterranean diet (MD) and a very low protein diet (VLPD) reduce protein carbamylation through reduction in urea levels in patients with chronic kidney disease (CKD). Methods This is a prospective, randomized, crossover controlled trial that investigated 60 patients with CKD grades 3B-4 (46 males, mean age of 67 years). The enrolled CKD patients were randomly assigned (1:1) to two different nutritional treatment arms: (i) 3 months of free diet (FD), 6 months of VLPD, 3 months of FD and 6 months of MD; and (ii) 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD. Blood levels of lysine (Lys) and homocitrulline (Hcit) and their ratio were used as markers of cyanate levels. Due to a lack of pre-existing data on the potential effects of different dietary regimens and in light of the exploratory nature of the study, no formal sample size estimation was carried out. Results At study completion, lower diastolic blood pressure and decreased serum levels of urea, sodium, phosphorus and parathyroid hormone, but higher serum levels of bicarbonate and haemoglobin, were noted with MD and VLPD. When compared with FD, both MD and VLPD were also associated with a decrease in serum Hcit levels and Hcit/Lys ratios (P

This position paper of the study group "Conservative treatment of Chronic Kidney Disease-CKD" of the Italian Society of Nephrology addresses major practical, unresolved, issues related to the conservative treatment of chronic renal disease. Specifically, controversial topics from everyday clinical nephrology practice which cannot find a clear, definitive answer in the current literature or in nephrology guidelines are discussed. The paper reports the point of view of the study group. Concise and practical advice is given on several common issues: renal biopsy in diabetes; dual blockade of the renin-angiotensin-aldosterone system (RAAS); management of iron deficiency; low protein diet; dietary salt intake; bicarbonate supplementation; treatment of obesity; the choice of conservative therapy vs. dialysis. For each topic synthetic statements, guideline-style, are reported.

Background Parathyroid hormone (PTH) has been associated with anemia only in dialysis patients with severe hyperparathyroidism. Whether an association between PTH and hemoglobin also exists in patients with chronic kidney disease not on dialysis (CKD-patients) is still unclear. In this study we evaluated the association between PTH and hemoglobin in CKD-patients without severe secondary hyperparathyroidism. Methods Hospitalized patients and outpatients (N = 979) were retrospectively evaluated and categorized according to PTH quartile and serum hemoglobin (

BACKGROUND Very low-protein intake during chronic kidney disease (CKD) improves metabolic disorders and may delay dialysis start without compromising nutritional status, but concerns have been raised on a possible negative effect on survival during dialysis. This study aimed at evaluating whether a very low-protein diet during CKD is associated with a greater risk of death while on dialysis treatment. METHODS This is an historical, cohort, controlled study, enrolling patients at dialysis start previously treated in a tertiary nephrology clinic with a very low-protein diet supplemented with amino acids and ketoacids (s-VLPD group, n = 184) or without s-VLPD [tertiary nephrology care (TNC) group, n = 334] and unselected patients [control (CON) group, n = 9.092]. The major outcome was survival rate during end-stage renal disease associated to s-VLPD treatment during CKD. The propensity score methods and Cox regression model were used to match groups at the start of dialysis to perform survival analysis and estimate adjusted hazard ratio (HR). RESULTS In s-VLPD, TNC and CON groups, average age was 67.5, 66.0 and 66.3 years, respectively (P = 0.521) and male prevalence was 55, 55 and 62%, respectively (P = 0.004). Diabetes prevalence differed in the three groups (P < 0.001), being 18, 17 and 31% in s-VLPD, CON and TNC, respectively. A different prevalence of cardiovascular (CV) disease was found (P < 0.001), being similar in TNC and CON (31 and 25%) and higher in s-VLPD (41%). Median follow-up during renal replacement therapy (RRT) was 36, 32 and 36 months in the three groups. Adjusted HR estimated on matched propensity patients was 0.59 (0.45-0.78) for s-VLPD versus CON. Subgroup analysis showed a lower mortality risk in s-VLPD versus matched-CON in younger patients (

Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial.This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients).CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P0.001) and sevelamer (P0.001), pre-dialysis bicarbonate levels (P0.001) and pre-dialysis blood K levels (P0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P.In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).

Cardiovascular (CV) disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD) patients. Although about half of the deaths are due to CV causes, only a minority are directly linked to myocardial infarction and it is estimated that cardiac arrest or cardiac arrhythmias account for about a quarter of all deaths registered in dialysis patients. Thus, simple non-invasive tools such as electrocardiogram (ECG) may detect those patients at increased risk for arrhythmias. The QT interval on the standard 12-lead ECG is the time from ventricular depolarization (Q wave onset) to cardiac repolarization completion (end of the T wave) and represents a marker of cardiac repolarization defects. Numerous studies suggest a direct association between QT abnormalities and poor prognosis in the general population, CKD patients and dialysis patients. Of note, multivariable adjustments for different traditional and CKD-specific risk factors for CV events attenuate but do not cancel these associations. We herein review the clinical significance of simple non-invasive tools such as the QT tract on ECG for detecting those patients at increased risk of CV event and possibly for treatment individualization.

Background: In non-dialysis patients (ND-CKD), C.E.R.A. has been extensively investigated in ESA-naïve subjects but no data are available on its efficacy after switch from other ESA. Methods: In this prospective, multicenter, open-label study lasting 24 weeks, ND-CKD patients (n = 157) receiving ESA were converted to C.E.R.A. at doses lower than recommended. Primary outcome was the prevalence of Hb target (11-12.5 g/dl). Results: Age was 73 ± 13 years and GFR was 26.2 ± 9.4 ml/min/1.73 m2; male gender, diabetes and prior cardiovascular disease were 49, 33 and 19%, respectively. Doses of darbepoetin (25 ± 16 µg/week, n = 124) and epoetin (5,702 ± 3,190 IU/week, n = 33) were switched to low dose C.E.R.A. (87 ± 17 µg/month). During the study, prevalence of Hb target increased from 60% to 68% at week-24, while that of Hb < 11 g/dl declined from 32% to 16% (p < 0.001). Hb increased from 11.3 ± 0.8 at baseline to 11.7 ± 0.9 g/dl at week-24 (p = 0.01) without changes in C.E.R.A. dose. Significant predictors of Hb increase were low BMI, low Hb and longer dosing intervals before switch. These factors also predicted the risk of Hb overshooting (Hb > 12.5 g/dl) occurring in 57 patients. Conclusions: In ND-CKD, conversion from other ESAs to C.E.R.A. is associated with a better anemia control induced by a greater Hb increase in patients previously treated with ESAs at extended dosing interval. This parameter should be considered when switching to long-acting ESA for its potential impact on the risk of overshooting.

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 antiproteinuric 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.

The control of sodium intake, and the implementation of low sodium diet in nephrology clinical practice is very low, is difficult when salt have been implicated as targets for manipulation to limit progression of kidney disease. It is well recognized that better control of blood pressure is important in mitigating the progression of CKD. We describe the effects of Very Low protein Diet on intake of Sodium, and, consequently, on proteinuria and blood pressure.

Background Nutritional treatment has always represented a major feature of CKD management. Over the decades, the use of nutritional treatment in CKD patients has been marked by several goals. The first of these include the attainment of metabolic and fluid control together with the prevention and correction of signs, symptoms and complications of advanced CKD. The aim of this first stage is the prevention of malnutrition and a delay in the commencement of dialysis. Subsequently, nutritional manipulations have also been applied in association with other therapeutic interventions in an attempt to control several cardiovascular risk factors associated with CKD and to improve the patient's overall outcome. Over time and in reference to multiple aims, the modalities of nutritional treatment have been focused not only on protein intake but also on other nutrients. Discussion This paper describes the pathophysiological basis and rationale of nutritional treatment in CKD and also provides a report on extensive experience in the field of renal diets in Italy, with special attention given to approaches in clinical practice and management. Summary Italian nephrologists have a longstanding tradition in implementing low protein diets in the treatment of CKD patients, with the principle objective of alleviating uremic symptoms, improving nutritional status and also a possibility of slowing down the progression of CKD or delaying the start of dialysis. A renewed interest in this field is based on the aim of implementing a wider nutritional therapy other than only reducing the protein intake, paying careful attention to factors such as energy intake, the quality of proteins and phosphate and sodium intakes, making today’s low-protein diet program much more ambitious than previous. The motivation was the reduction in progression of renal insufficiency through reduction of proteinuria, a better control of blood pressure values and also through correction of metabolic acidosis. One major goal of the flexible and innovative Italian approach to the low-protein diet in CKD patients is the improvement of patient adherence, a crucial factor in the successful implementation of a low-protein diet program.

Background Dietary treatment is helpful in CKD patients, but nutritional interventions are scarcely implemented. The main concern of the renal diets is its feasibility with regards to daily clinical practice especially in the elderly and co-morbid patients. This study aimed to evaluate the effects of a pragmatic, step-wise, personalized nutritional support in the management of CKD patients on tertiary care. Methods This is a case-control study. It included 823 prevalent out-patients affected by CKD stage 3b to 5 not-in-dialysis, followed by tertiary care in nephrology clinics; 305 patients (190 males, aged 70 ± 12 years) received nutritional support (nutritional treatment Group, NTG); 518 patients (281 males, aged 73 ± 13 years) who did not receive any dietary therapy, formed the control group (CG). In the NTG patients the dietary interventions were assigned in order to prevent or correct abnormalities and to maintain a good nutritional status. They included manipulation of sodium, phosphate, energy and protein dietary intakes while paying special attention to each patient’s dietary habits. Results Phosphate and BUN levels were lower in the NTG than in the CG, especially in stage 4 and 5. The prevalence of hyperphosphatemia was lower in the NTG than in CG in stage 5 (13.3 % vs 53.3 %, p

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 SBPVon 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

Background Predictors of haemoglobin (Hb) levels and resistance to erythropoiesis-stimulating agents (ESAs) in dialysis patients have not yet been clearly defined. Some mainly uncontrolled studies suggest that online haemodiafiltration (HDF) may have a beneficial effect on Hb, whereas no data are available concerning online haemofiltration (HF). The objectives of this study were to evaluate the effects of convective treatments (CTs) on Hb levels and ESA resistance in comparison with low-flux haemodialysis (HD) and to evaluate the predictors of these outcomes. Methods Primary multivariate analysis was made of a pre-specified secondary outcome of a multicentre, open-label, randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: online pre-dilution HF (36 patients) or online pre-dilution HDF (40 patients). Results CTs did not affect Hb levels (P = 0.596) or ESA resistance (P = 0.984). Hb correlated with polycystic kidney disease (P = 0.001), C-reactive protein (P = 0.025), ferritin (P = 0.018), ESA dose (P < 0.001) and total cholesterol (P = 0.021). The participating centres were the main source of Hb variability (partial eta2 0.313, P < 0.001). ESA resistance directly correlated with serum ferritin (P = 0.030) and beta2 microglobulin (P = 0.065); participating centres were again a major source of variance (partial eta2 0.367, P < 0.001). Transferrin saturation did not predict either outcome variables (P = 0.277 and P = 0.170). Conclusions In comparison with low-flux HD, CTs did not significantly improve Hb levels or ESA resistance. The main sources of variability were participating centres, ESA dose and the underlying disease.

We have already demonstrated that in chronic hemodialysis (HD) patients, the cyclic variations in both hydration status and blood pressure are responsible for changes in pulse wave velocity (PWV). The aim of this study is to verify whether the cyclic variation of PWV influences mortality in dialysis patients. We studied 167 oligoanuric (urinary output o500 mL/day) patients on chronic standard bicarbonate HD for at least 6 months. They performed 3 HD sessions of 4 hours per week. Patients were classified into 3 groups: normal PWV before and after dialysis (LL); high PWV before and normal PWV after dialysis (HL); and high PWV before and after dialysis (HH). The carotid-femoral PWV was measured with an automated system using the foot-to-foot method. Analysis of variance was used to compare the different groups. The outcome event studied was all-cause mortality and cardiovascular mortality. The PWV values observed were LL in 44 patients (26.3%); HL in 53 patients (31.8%); and HH in 70 patients (41.9%). The 3 groups of patients are homogenous for sex, age, and blood pressure. The HH group had a higher prevalence of (Po0.001) ASCVD. It is interesting that the distribution of patients in the 3 groups is correlated with the basal value of PWV. In fact, when the basal measure of PWV is elevated, there is a higher probability that an HD session cannot reduce PWV (o12 ms). A total of 53 patients (31.7%) died during the follow-up of 2 years: 5 patients in the LL group (11.4%); 16 in the HL group (30.2%); and 32 in the HH group (50.7%) (LL vs. HL, P =0.047; LL vs. HH, Po0.00001; HL vs. HH, P=0.034). We evidence for the first time that different behaviors of PWV in dialysis subjects determine differences in mortality.

Despite the clinical importance of pulse-wave velocity (PWV), there are no standards for accurate carotid-radial pulse-wave measurement in uremic patients with respect to carotid-femoral measurement. We assessed the reproducibility of PWV values using the carotid-radial PWV measurement. We have measured the carotid-femoral PWV and carotid-radial PWV with an automated system (Pulse Pen, DiaTecne) using 2 different blind operators in 105 hemodialysis (HD) patients. The carotid-femoral waveforms were acquired by the first blind operator simultaneously with 2 pressure-sensitive transducers and the transit time of the pulse was calculated using the system software. Similarly, the second blind operator acquired the carotid-radial waveforms. The two operators performed 2 consecutive measurements from the same subject, in a random order. In fact, after the first operator had completed 2 consecutive measurements from 1 subject, all of the sensors were detached, and the second operator attached sensors again to the same subject. The measurements were performed during interval of a midweek dialysis-free day. To evaluate the reproducibility of the system, both within-observer and between-observer analyses were performed. We studied 105 dialysis patients (HD) and 20 controls. All HD patients had three dialysis sessions lasting at least 4 h/wk. A total of 28 patients (26.7%) had diabetic nephropathy. The mean age of HD was 64.6 16.1 years, the body weight was 71.1 15.1 kg, and the height was 164.6 6.1 cm. All population studied is referral at a tertiary care from at least 6 months (mean 11.1 2.1 months). A total of 45% of patients are smokers or ex-smokers. The PWV of carotid-femoral is 8.58 3.99 and the PWV of carotid-radial is 8.70 4.01 m/sec, respectively, by the first and the second operator; the difference of PWV (femoral-radial measure) is 0.037 0.99 m/sec. The linear correlation of carotid-femoral vs. carotid-radial PWV measurements is the highest (R 2 = 0.90). The results regarding reproducibility, including mean differences and standard deviations, standard errors, and correlation coefficients were analyzed for each regional PWV value for the between-observer and within-observer studies. All of the measurements showed significant correlation coefficients, ranging from 0.94 to 0.98. The reproducibility of regional PWV values for 2 consecutive measurements from the same subject was also analyzed using Bland-Altman plots, with the reproducibility expressed as the mean difference and 2 standard deviations between the measurements obtained by the 2 operators during carotid-femoral and carotid-radial measurements. Carotid-radial PWV measurement provides an accurate analysis with a high reproducibility with respect to carotidfemoral PWV measurement, and it can be used for arterial stiffness analysis in hemodialysis patients.

Background. Kt/Vurea was established as an index of haemodialysis (HD) adequacy. The use of Vurea as a normalizing factor has been questioned, and alternative parameters such as body weight 0.67 (W 0.67 ), body surface area (BSA), resting energy expenditure (REE), high metabolic rate organ (HMRO) mass, liver size (LV) and more recently, bioelectrical resistance (R), an independent and directly measurable biological parameter, were proposed as alternative methods for scaling dialysis dose. Methods. The present study aimed to prospectively evaluate the predictive power of some demographic, anthropometric, bioelectrical (BIA) and biochemical parameters, of seven scaling parameters, namely Vurea, as derived from the Watson et al. formulae, W 0.67 , BSA, REE, HMRO, LV and R and of eight HD adequacy indices [single-pool variable-volume Kt/Vurea, computed using the Daugirdas equation, its rescaled equivalents (Kt/W 0.67 , Kt/BSA, Kt/ REE, Kt/HMRO, Kt/LV and Kt/R) and Kt] on long-term survival of a cohort of 328 incident white HD patients. All individuals underwent periodical (every 3 months) biochemical evaluations and single-frequency BIA measurements, injecting 800 μA at 50 kHz alternating sinusoidal current with a standard tetrapolar technique. Results. A first Cox regression analysis, testing the predictive power of some demographic, anthropometric, BIA and biochemical parameters, and of the eight HD adequacy indices on long-term survival of the patients, showed that only higher serum creatinine (Scr) levels (P < 0.0001) and lower Kt/R values (P < 0.04) were significant outcome predictors. As Kt was shown not to be an outcome predictor, a second Cox regression analysis, testing the predictive power of the same demographic, anthropometric, BIA and biochemical parameters, and of the seven scaling parameters on long-term survival of the patients, was built. It showed that only higher Scr levels (P < 0.0001) and higher R values (P < 0.04) were significant outcome predictors. Kaplan-Meier survival analyses of the patients stratified into two groups, respectively, according to the first quartile of R values (0.0-467.8 Ohm), the fourth quartile of Kt/R values (98-106 ml/Ohm) and the first quartile of Scr levels (0.0-11.6 mg/dl) showed a significantly higher long-term survival in the groups of patients having R values above the first quartile (P < 0.04), Kt/R values below the fourth quartile (P < 0.03) and Scr levels above the first quartile (P < 0.0001). Conclusions. Kt/R, R and Scr were independent significant predictors of long-term-survival in incident HD patients: R is related to the fluid status, whereas Scr, which reflects the lean body mass, seems to suggest that body composition is more important than body weight and/or body mass index. Further work is required to develop these concepts and to translate them into rigorous outcome-based adequacy targets suitable for clinical usage.

BACKGROUND The accurate measurement of total body water (TBW) requires isotopic dilution techniques that are not easily applicable to the clinical setting. Therefore, indirect methods of estimating TBW are commonly employed, such as bioelectrical impedance analysis (BIA) and anthropometry. In the human body, >90% of the measured impedance is composed of resistance (R). METHODS The aim of the present study was to compare TBW estimated by means of two anthropometric equations (by Watson and Hume) with TBW obtained by BIA (equations proposed by Sun et al.) in a group of white disease-free individuals (n = 3625, 1860 men and 1765 women) and white haemodialysis (HD) patients (n = 688, 443 men and 245 women). They underwent one single-frequency BIA measurement, on the nondominant side of the body, injecting an 800-muA and 50-kHz alternating sinusoidal current with a standard tetrapolar technique. The BIA variable measured was R. RESULTS Among them, a selection of disease-free individuals (n = 481) and HD patients (n = 270), pair-matched by age, body weight and height, after stratification by gender, was made. When comparing the four pair-matched groups, it was found that (1) TBW was not different (disease-free men versus HD men; disease-free women versus HD women) when using anthropometric equations, which utilize quite identical parameters (age, body weight and height); (2) R was statistically significantly different in the four groups (511 +/- 58 SD Omega in disease-free men versus 558 +/- 80 in HD men, P < 0.0001; 593 +/- 70 Omega in disease-free women versus 615 +/- 100 in HD women, P < 0.02) and (3) therefore, TBW was statistically significantly different only when applying BIA equations (P < 0.0001 and 0.05, respectively). CONCLUSIONS The present study demonstrates that anthropometric equations for the estimation of TBW can be used only within a specific population in order to assess individual differences; they cannot be used in order to compare two different populations.

Postdialytic rebound (PDR) of plasma solutes is a relevant drawback of intermittent hemodialysis, but its pathophysiological process remains undefined. We assessed the independent effects of efficiency and length of dialytic session on PDR of urea, phosphate, and potassium.Uremic patients were evaluated at the beginning and end of dialysis and after 180 minutes in 2 randomized crossover studies. In study 1, we compared the effect of standard versus higher efficiency acetate-free biofiltration (AFB) while maintaining the same duration of 4 hours. In study 2, we compared the effect of 3- versus 5-hour AFB sessions while maintaining similar efficiency.In study 1, greater Kt/V (1.49 +/- 0.20 versus 1.22 +/- 0.15; P0.0001) was coupled with significant increases in both absolute removal and PDR of urea and phosphate (PDR of urea, +45% versus +29%; PDR of phosphate, +79% versus +52%), but not of potassium. Similarly, in study 2, shortening the AFB session while maintaining similar absolute removal and Kt/V (1.28 +/- 0.09 versus 1.31 +/- 0.09) significantly increased PDR of urea and phosphate (PDR of urea, +32% versus +19%; PDR of phosphate, +63% versus +36%), but not of potassium. In both studies, greater PDRs of urea and phosphate were associated with estimated greater removal of these solutes per hour.The rate of removal of phosphate and urea is a critical determinant of their PDR; conversely, potassium is not influenced by removal rate, likely because of its marked cell compartmentalization.

We will present our experience and our preliminary data about the correlation between cardiac calcification and QT interval (and QT dispersion) in uraemia. We studied 32 haemodialysis (HD) patients (age 69 ± 16 years, time on dialysis 32 ± 27 months) and 12 chronic kidney disease stage 4 (CKD-4) patients (age 66 ± 17 years, uraemia duration 38 ± 16 months). The patients were characterized by a good mineral control, as shown by serum phosphate levels (3.6 ± 1.3 mg/dl in CKD-4 and 4.3 ± 1.6 mg/dl in HD patients) and Ca × P product (46 ± 17 and 49 ± 16 mg2/dl2, respectively). The parathyroid hormone levels were higher in HD than CKD-4 patients (p < 0.0001). A TC score >400 was found to be highly prevalent in both groups. Significantly more HD patients (62.5%) showed cardiac calcification than CKD-4 patients (33%; p = 0.01). The patients were matched for TC scores higher or lower than 400. The two groups differed by gender (p < 0.05), age (p = 0.026), frequency of diabetes mellitus (p < 0.01), uraemia follow-up period (p < 0.001), low-density lipoprotein cholesterol level (p = 0.009), Ca × P product (p = 0.002), parathyroid hormone level (p < 0.0001), and corrected QT dispersion (p < 0.0001). The QT interval was higher in HD and CKD-4 patients with higher TC scores (approximately 11%), but QT interval dispersion was significantly higher in patients with TC scores >400. QT dispersion showed a linear correlation with TC scores in both groups (r = 0.899 and p < 0.0001 and r = 0.901 and p < 0.0001). Male gender, age, time (months) of uraemia, low-density lipoprotein cholesterol, albumin, calcium × phosphorus product, parathyroid hormone, and TC score are important determinants of QT dispersion. Our data show that it is possible to link dysrhythmias and cardiac calcification in uraemic patients.

Summary 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.

Background: Female gender is associated with high erythropoietin (EPO) resistance in end-stage renal disease. The aim of our study was to investigate the roles of age and menstrual status in this relationship. Methods: Cross-sectional analysis of registry data for 3,224 hemodialysis adults treated with EPO. Data collection included gender, age, weight, height, dialytic age, hemoglobin, EPO dose, and, for women with ages 25–44 only, also information on menstrual status and iron homeostasis. EPO resistance index (ERI) was calculated as EPO dose per kilogram BW/hemoglobin. Results: Men and women had not significantly different hemoglobin and significantly different EPO dose per kilogram weight (women vs. men, +18.2%, p < 0.001). Thus, ERI was higher in women than in men (+19.5%, p < 0.001). The gender-associated difference in ERI linearly decreased along age groups: +30.9% for ages 25–44, +23.2% for ages 45–64, and +14.2% for ages 65–84 (p < 0.05 for interaction between age and gender-associated difference in ERI). Within the subgroup of women with ages 25–44, women with menses in comparison to women without had 44.6% higher ERI (p < 0.01) due to combination of lower hemoglobin (p < 0.05) with higher EPO dose (p < 0.001). Women with menses had also lower serum iron, transferrin saturation, and serum ferritin (p < 0.001). Conclusion: The gender-associated difference in ERI is lower with increasing patients’ age. The large difference between young men and women is due to women with menses who have iron deficiency more frequently than women without periods.

Background. Non-anaemic haemodialysis (HD) patients are potentially more prone to the adverse effects of ultrafiltration-induced haemoconcentration. No study, however, has assessed the effects of dialytic session on haemoglobin (Hb) levels in these patients. Methods. The levels of Hb and total protein before, at the end (T0) and up to 120 min (T120) after the third HD session of the week were compared in non-anaemic (Hb >13 g/dl, n ¼ 14, NOR) and anaemic (Hb ¼ 11–12 g/dl, n ¼ 18, LOW) HD patients. Results. The intradialytic weight loss was similar in the two groups (4.0 ± 0.9 and 4.1 ± 0.9% body weight). During the treatment, Hb levels increased to the same extent in both groups (from 14.4 ± 1.2 to 16.3 ± 1.9 g/dl in NOR, and from 11.4 ± 0.8 to 12.7 ± 0.9 g/dl in LOW) in the presence, presumably, of a smaller plasma volume in NOR, whereas the increment of total protein was greater in NOR (from 7.1 ± 0.2 to 9.6 ± 0.5 g/dl) than in LOW (from 7.3 ± 0.6 to 8.7 ± 0.8 g/dl) (P < 0.0001). At T120, the Hb decline in NOR was almost double that measured in LOW (� 9.2 ± 3.0 vs � 4.7 ± 2.4%, P < 0.001). Consequently, Hb concentration did not differ from the pre-dialytic value in NOR (P ¼ 0.10), but persisted higher in LOW (P < 0.005). The extent of the postdialytic decrement of Hb was inversely related to the total protein values at T0 (r ¼� 0.547, P ¼ 0.0012). Conclusions. This study indicates that in NOR: (i) the extent of intradialytic increment of Hb is limited by a greater intradialytic plasma refilling; (ii) the greater plasma refilling persists after the end of dialysis, with the restoration of pre-dialytic Hb levels within the initial 2 h; and (iii) the force driving this phenomenon resides mainly in the larger changes of total protein concentration.

Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure.BackgroundThe aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF).MethodsWe monitored for 2years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance ≤25mL/min), randomized to either low protein diet (LPD) group (0.6g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels.ResultsThe achieved protein intake after 6months was 0.79 ± 0.02g/kg body weight/day and 0.50 ± 0.02g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 ± 0.2g/dL and 11.5 ± 0.3g/dL). EPO dose, that was similar at baseline (62.4 ± 9.6 UI/kg body weight/week and 61.8 ± 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 ± 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 ± 55pg/mL to 118 ± 16pg/mL (P < 0.0001) in VLPD and did not change in LPD.ConclusionIn patients with advanced CRF, an effective decrease of protein intake of 0.3g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.