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Bone mineral abnormalities (defined as Chronic Kidney Disease Mineral Bone Disorder; CKD-MBD) are prevalent and associated with a substantial risk burden and poor prognosis in CKD population. Several lines of evidence support the notion that a large proportion of patients receiving maintenance dialysis experience a suboptimal biochemical control of CKD-MBD. Although no study has ever demonstrated conclusively that CKD-MBD control is associated with improved survival, an expanding therapeutic armamentarium is available to correct bone mineral abnormalities. In this position paper of Lombardy Nephrologists, a summary of the state of art of CKD-MBD as well as a summary of the unmet clinical needs will be provided. Furthermore, this position paper will focus on the potential and drawbacks of a new injectable calcimimetic, etelcalcetide, a drug available in Italy since few months ago.

Uremia is a systemic inflammatory condition characterized by a combination of oxidative burst, uremic toxicity, uremic dyslipidemia, endothelial dysfunction and oxidative stress resulting from dysfunctional mitochondrial electron transfer generating reactive oxygen species. These compounds induce oxidative modifications of carbohydrates (AGEs), proteins, lipids and DNA, in turn recognized as DAMPs by Toll-like receptors (TLRs), which in end-stage renal disease (ESRD) are upregulated in many cell types including macrophages and neutrophils. All the inflammatory derangements typical of ESRD lead to an increased cardiovascular risk in dialysis patients. Unfortunately, the technological innovations in dialysis techniques have not given rise to a better prognosis for patients with ESRD, probably because they have had no favorable effect on inflammation in the uremic milieu. Presenting a recent review by Baragetti and coworkers published in Am J Nephrol 2017 and the results of a PubMed search with “antiinflammatory drug hemodialysis”, “oxidative stress drugs hemodialysis” and “endothelial dysfunction drug hemodialysis” as keywords, we would like to offer a novel and innovative approach to targeting uremic inflammation considering data from clinical trials.

Introduction: A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single-pool variable-volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients. Methods: Thirty-four patients on thrice-weekly HD were studied during 240 dialysis sessions. All patients were dialyzed with a nominal total calcium concentration of 1.50 mmol/L. The main assumption of the model is that the calcium distribution volume is equal to the extracellular volume during dialysis. This hypothesis is assumed valid if measured and predicted end dialysis plasma water ionized calcium concentrations are equal. A difference between predicted and measured end-dialysis ionized plasma water calcium concentration is a deviation on our main hypothesis, meaning that a substantial amount of calcium is exchanged between the extracellular volume and a nonmodeled compartment. Findings: The difference between predicted and measured values was 0.02 mmol/L (range −0.08:0.16 mmol/L). With a mean ionized dialysate calcium concentration of 1.25 mmol/L, calcium mass balance was on average negative (mean ± SD −0.84 ± 1.33 mmol, range −5.42:2.75). Predialysis ionized plasma water concentration and total ultrafiltrate were the most important predictors of calcium mass balance. A significant mobilization of calcium from the extracellular pool to a nonmodeled pool was calculated in a group of patients. Discussion: The proposed single pool variable-volume Calcium kinetic model is adequate for prediction and quantification of intradialysis calcium mass balance, it can evaluate the eventual calcium transfer outside the extracellular pool in clinical practice.

Etelcalcetide hydrochloride (also known as AMG 416) is a new, second generation, long-acting calcimimetic agent that is administered intravenously. In November 2016 it received its first approval in the UE for the treatment of secondary hyperparathyroidism (SHPT) in adult haemodialysis patients. This article summarizes the results of pre-clinical and clinical studies which demonstrated that Etelcalcetide decreases effectively PTH levels. Although questions about this new compound remain open, and further studies are required to assess clinical hard outcomes as well as long term efficacy and safety, Etelcalcetide represents a new therapeutic option for the challenging treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).

Background/Aims: This study aimed to evaluate total and sudden death (SD) in a cohort of dialysis patients, comparing hemodialysis (HD) vs. peritoneal dialysis (PD). Methods: This is a multicenter retrospective cohort study. Results: Deaths were 626 out of 1,823 in HD and 62 of 249 in PD patients. HD patients had a greater number of comorbidities (p < 0.05). PD patients had a lower risk of death than HD patients (p < 0.001); however, the advantage decreased with time (p < 0.001). Mortality predictors were left ventricular ejection fraction (LVEF) ≤35%, older age, ischemic heart disease, diabetes mellitus, previous stroke, and atrial fibrillation (p < 0.03). SDs were 84:71 in HD and 13 in PD population (12.1 and 22.8% of all causes of death, respectively). A non-significant risk of SD among PD compared to HD patients was detected. SD predictors were older age, ischemic heart disease, and LVEF ≤35% (p < 0.05). Conclusions: HD patients showed a greater presence of comorbidities and reduced survival compared to PD patients; however, the incidence of SD does not differ in the 2 populations. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=464347.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Within the framework of the LUST trial (LUng water by Ultra-Sound guided Treatment to prevent death and cardiovascular events in high-risk end-stage renal disease patients), the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis Transplant Association established a central core lab aimed at training and certifying nephrologists and cardiologists participating in this trial. All participants were trained by an expert trainer with an entirely web-based programme. Thirty nephrologists and 14 cardiologists successfully completed the training. At the end of training, a set of 47 lung ultrasound (US) videos was provided to trainees who were asked to estimate the number of B-lines in each video. The intraclass correlation coefficient (ICC) for the whole series of 47 videos between each trainee and the expert trainer was high (average 0.81 ± 0.21) and >0.70 in all but five cases. After further training, the five underperforming trainees achieved satisfactory agreement with the expert trainer (average post-retraining ICC 0.74 ± 0.14). The Bland-Altman plot showed virtually no bias (difference between the mean 0.03) and strict 95% limits of agreement lines (-1.52 and 1.45 US B-lines). Only four cases overlapped but did not exceed the same limits. Likewise, the Spearman correlation coefficient applied to the same data series was very high (r = 0.979, P < 0.0001). Nephrologists and cardiologists can be effectively trained to measure lung congestion by an entirely web-based programme. This web-based training programme ensures high-quality standardization of US B-line measurements and represents a simple, costless and effective preparatory step for clinical trials targeting lung congestion.

A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single-pool variable-volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients.Thirty-four patients on thrice-weekly HD were studied during 240 dialysis sessions. All patients were dialyzed with a nominal total calcium concentration of 1.50 mmol/L. The main assumption of the model is that the calcium distribution volume is equal to the extracellular volume during dialysis. This hypothesis is assumed valid if measured and predicted end dialysis plasma water ionized calcium concentrations are equal. A difference between predicted and measured end-dialysis ionized plasma water calcium concentration is a deviation on our main hypothesis, meaning that a substantial amount of calcium is exchanged between the extracellular volume and a nonmodeled compartment.The difference between predicted and measured values was 0.02 mmol/L (range -0.08:0.16 mmol/L). With a mean ionized dialysate calcium concentration of 1.25 mmol/L, calcium mass balance was on average negative (mean ± SD -0.84 ± 1.33 mmol, range -5.42:2.75). Predialysis ionized plasma water concentration and total ultrafiltrate were the most important predictors of calcium mass balance. A significant mobilization of calcium from the extracellular pool to a nonmodeled pool was calculated in a group of patients.The proposed single pool variable-volume Calcium kinetic model is adequate for prediction and quantification of intradialysis calcium mass balance, it can evaluate the eventual calcium transfer outside the extracellular pool in clinical practice.

Cardiovascular disorders are the leading cause of death in dialysis patients, with 27% of all deaths attributable to arrhythmic mechanisms that are at least partly due to variations in serum potassium levels. Recently, Karaboyas et al compared the two most common dialysate prescriptions (2 vs 3 mEq/L) in terms of the associated risk of death and arrhythmia. No meaningful differences were observed in mortality and arrhythmia outcomes. However, a serum potassium level higher than 5.6 mEq/L was associated with higher mortality and a higher arrhythmia risk. Moreover, there was a direct, albeit small, association with +0.09 mEq/L serum potassium and every +1 mEq/L dialysate potassium, suggesting the utility of strategies other than altering the dialysate potassium concentration in order to control potassium levels. Two new potassium-binding drugs are now under evaluation which hopefully will be found to have greater tolerability than the widely used sodium polystyrene sulfonate, which is associated with important gastrointestinal side effects. Patiromer was approved in the United States in 2015, while sodium zirconium cyclosilicate 9 could really be the most interesting molecule, considering its action in the higher gastrointestinal tract without any side effects. However, more studies are required, also in dialysis 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).

Nonostante gli sforzi in atto, la percentuale di pazienti che utilizzano un catetere venoso centrale (CVC) per eseguire il trattamento emodialitico è attualmente troppo elevata e ben superiore al 10% anche in Italia. Le complicanze associate all’uso dei CVC sono numerose, ma le più temibili sono quelle infettive, responsabili di significative morbilità e mortalità. Una recente meta-analisi di Zhao ha riportato come, in termini di prevenzione delle infezioni correlate al CVC, il lock con citrato sia risultato migliore rispetto all’eparina, quando utilizzato in associazione a sostanze dotate di attività anti-microbica (gentamicina o taurolidina, per esempio) e a concentrazioni basse-moderate. Inoltre, l’utilizzo del citrato ridurrebbe gli episodi di sanguinamento, mentre non sono emerse differenze in termini di incidenza di infezioni dell’exit-site e di mantenimento della pervietà del CVC. I risultati emersi da un recente trial prospettico hanno sottolineato l’importanza di un’adeguata gestione dell’emergenza del CVC e del CVC stesso. Infatti, l’utilizzo di clorexidina al 2% per la disinfezione dell’exit-site e l’utilizzo di tamponi sterili con alcol al 70% per eseguire lo “sfregamento del CVC” permettevano di ridurre del 20% l’incidenza delle infezioni correlate al CVC, oltre a garantire una minore necessità di terapia antibiotica e una ridotta ospedalizzazione per sepsi e complicanze infettive CVC-correlate. Tuttavia, sono necessari nuovi studi e provvedimenti per poter migliorare ulteriormente la prognosi dei pazienti che utilizzano un CVC come accesso vascolare per emodialisi.

BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of

Il calciomimetico Cinacalcet è ormai in uso da alcuni anni per il trattamento dell'iperparatiroidismo secondario (IPTS) nei pazienti dializzati, permettendo una buona riduzione dei livelli di paratormone. Nell'ottica di valutare un suo possibile effetto benefico nel migliorare la prognosi cardio-vascolare dei pazienti dializzati, è stato condotto lo studio randomizzato “Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events” (EVOLVE). Sono stati randomizzati a ricevere Cinacalcet o placebo 3883 pazienti dializzati affetti da iperparatiroidismo secondario moderato-severo, valutando come end-point compositi primari la mortalità e gli episodi di infarto mio-cardico, l'ospedalizzazione per angina instabile, lo scompenso cardiaco ed eventi vascolari periferici. Nell'analisi “intention-to-treat”, a causa di una bassa potenza statistica, non sono state rilevate differenze significative tra i due bracci dello studio, a fronte di una più elevata incidenza di ipocalcemia, nausea e vomito nei soggetti in terapia con il calciomimetico. I dati dello studio EVOLVE hanno sicuramente deluso la comunità nefrologica, che si sarebbe aspettata dei risultati positivi. La mancanza di risultati conclusivi e i costi elevati suggeriscono un uso giudizioso del Cinacalcet. Non di meno, anche se mancano dati conclusivi su “hard end-point”, ci sembra poco saggio negare strategie terapeutiche che includano il Cinacalcet ai pazienti con severo IPTS con elevati livelli di PTH (PTH >800 pg/mL) refrattari alla terapia standard e/o ipercalcemia e/o calcifilassi e/o elevato rischio chirurgico alla paratiroidectomia.

The calcimimetic cinacalcet is now being used for years to treat secondary hyperparathyroidism (SHPT) in dialysis patients, allowing a good reduction in PTH levels. In order to evaluate a possible beneficial effect on cardiovascular prognosis, a randomized trial, the EVOLVE (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), was conducted in 3,883 dialysis patients affected by moderate to severe SHPT.Patients were randomly assigned to receive cinacalcet or placebo. The primary composite endpoint evaluated was time until death, myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular events. Due to a low statistical power, there was no significant difference between the two arms of the study in the intention-to-treat analysis, despite a higher incidence of hypocalcaemia, nausea, and vomiting in patients treated with cinacalcet.The results of the EVOLVE study have certainly disappointed the nephrological community that would have expected ...

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

Mortality risk scores for hemodialysis patients have been developed also in the past, but with low clinical applicability. Floege has recently developed a score in 11.500 hemodialysis incident European patients, able to predict mortality risk after 1 and 2 years. The principal determinants of the score were: older age, low body mass index, history of cancer, high levels of C-reactive protein and low levels of albumin. The relevance of the score is due to its high applicability also to an external cohort of hemodialysis patients (the DOPPS study patients). The increased incidence of cancers in hemodialysis patients represents another important situation, in which we need to improve our everyday clinical practice, especially for cancers frequent in dialysis patients (kidney/renal pelvis and bladder), in order to apply adequate screening procedures.

Background: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. Methods: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range &lsqb;TiR&rsqb;) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. Results: Baseline results were calculated with 10 000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was &U20AC;50 012 per LY and &U20AC;67 361 per QALY, while, if dialysis costs were not included, the ICER was &U20AC;23 473 per LY and &U20AC;31 616 per QALY. Conclusions: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

Background. Hyperphosphataemia in patients on haemodialysis (HD) can lead to, or worsen, secondary hyperparathyroidism (with associated bone disease) and extra-skeletal calcifications associated with increased cardiovascular morbidity and mortality. MCI-196 is a new, non-absorbed, non-calcium-based phosphate binder. The aim of this study was to determine the effect of three fixed doses of MCI-196, on serum phosphorus level and other parameters relevant to HD patients. Methods. A total of 120 chronic kidney disease (CKD) stage 5 patients on HD and with the serum phosphorus level >2.1 mmol/l were randomized to receive double-blind treatment with either 3, 6 and 9 g/day MCI-196 or placebo for 3 weeks. Results. Serum phosphorous decreased in all three treatment groups (−0.038, −0.268 and −0.257 mmol/l in the 3, 6 and 9 g/day groups, respectively). The difference between treatment and placebo groups was significant for the 6 and 9 g/day groups (P < 0.05 in both cases). Changes in the mean serum calcium were minimal and without relevant differences between groups. However, calcium– phosphorus product (Ca × P) was significantly reduced in the 6 and 9 g/day groups P < 0.05). MCI-196 at all doses decreased serum intact PTH between baseline and endpoint, and differences between treatment groups and placebo were statistically significant for the 3 and 9 g/day groups (P < 0.02 in both cases). Both serum total and LDL cholesterol decreased significantly in all treatment groups compared to placebo (by 0.71–1.05 mmol/l, for total cholesterol and 0.68–0.94 mmol/l for LDL cholesterol P < 0.001 in all cases). There was minimal change in serum HDL cholesterol. MCI-196 at all doses decreased significantly serum uric acid between baseline and endpoint compared to placebo (P < 0.005 in all cases). The drug was well tolerated. Conclusion. MCI-196 significantly reduced serum phosphorus, Ca × P and PTH, without effecting serum calcium levels. The additional reduction in total cholesterol and LDL cholesterol indicates a possible dual mechanism of action of MCI-196 that has the potential to reduce cardiovascular morbidity in CKD stage 5 patients.

The Italian national health system funds universal health care through general taxation, but health services are provided by local institutions. This study examines the epidemiology, provision, and funding of renal replacement therapy (RRT) in Italy. In 2001, prevalence and incidence of RRT in Italy were 0.083% and 0.014%, respectively. A 1999 donation law markedly increased renal transplantation rates. Italy spends 8.3% of its GDP on health care; 1.8% is for end-stage renal disease (ESRD) patients, who represent 0.083% of the general population. The reorganization of the NHS requires attention from the health community so that economic and geographic health disparities are not exacerbated.

BACKGROUND Peritoneal membrane function can be assessed using the peritoneal equilibration test (PET) and similar tests, but these are almost always complicated to use, require a considerable amount of working time and their results cannot always be easily interpreted. Ionic conductivity is a measure of the ability of an electrolyte solution to conduct electricity. We tested the hypothesis that the ionic conductivity of peritoneal dialysate can be used to evaluate peritoneal membrane function in peritoneal dialysis patients. METHODS We measured the ionic conductivity and classic biochemical parameters of peritoneal dialysate in 69 patients during a modified PET and compared their ability to evaluate peritoneal membrane function and to diagnose ultrafiltration failure (UFF). RESULTS Ionic conductivity was correlated well with classical parameters of peritoneal transport as glucose reabsorption of glucose (D/D0: r(2) = 0.62, P < 0.0001) and creatinine transport (D/PCreat: r(2) = 0.72, P < 0.0001). Twelve patients (17%) experienced UFF and, in them, the ionic conductivity area under the receiver-operating characteristic curve was 0.91 (95% confidence interval: 0.81-0.96) with sensitivity of 1.00 and specificity of 0.84 at a cut-off value of 12.75 mS/cm. CONCLUSIONS These findings indicate that the ionic conductivity of peritoneal dialysate can be used as a new screening tool to evaluate peritoneal membrane function.

Intra-Dialysis Hypotension (IDH) is one of the main hemodialysis related complications, occurring in 25-30% of the sessions. The factors involved in the onset of hypotension in patients undergoing dialysis are due both to clinical conditions (e.g. presence of vascular or cardiac diseases, neuropathology, anemia) and treatment settings such as temperature of the dialysate, sodium concentration, buffer composition, ultrafiltration rate, etc. The patient's peculiar reaction to the treatment implies difficulties in preventing IDH episodes. This work explores the possibility to use a multivariate analysis of clinical data to quantify the risk to develop IDH at the beginning of each session. The study is framed in the DialysIS project (Dialysis therapy between Italy and Switzerland) funded by INTERREG - Italy - Switzerland and Co-funded by European Union. Data referring to a total of 516 sessions performed on 70 adult patients undergoing dialysis treatment (50 patients enrolled at A. Manzoni Hospital Lecco, Italy and 20 patients at Regional Hospital of Lugano, Switzerland) were collected. Clinical prescriptions, hydration status, dialysis machine data and hematochemical data were recorded and stored in a unique flexible structured MySQL® database. A statistical analysis was performed to find the potential risk factor related to IDH onset. IDH episodes were automatically detected during the monitored sessions, according to the literature criteria. Patients suffering from IDH in 2 or more sessions were classified as Hypotension Prone (HP), the others as Hypotension Resistant (HR). Initial values of potassium concentration (K+), systolic (SBP) and diastolic (DBP) blood pressure, and weight gain (ΔW) from the end of the previous treatment result to be statistically different between the HP and HR groups. A new index, J, was defined as a weighted patient-specific combination of these parameters and calculated for each session of each patient. The weight of the index coefficients can be dynamically adjourned based on the longitudinal analysis of (K+), SBP, DBP, and ΔW. The results reported in this paper were calculated based on a longitudinal analysis of a minimum of three sessions for each patient. The accuracy of the J index in predicting IDH events has been evaluated and quantified in terms of percentage number of predicted IDH events, with respect to the total number of IDHs. Values of J index higher than 1 point out the risk of IDH onset. J allows the prediction of 100% of IDH episodes using 5 sessions, the 90% using 3 sessions. More specifically, at Lecco Hospital 43 IDH events were detected by the automatic system of which 100% and 95% were respectively predicted by the new index calculated using 5 or 3 sessions. Similarly, at Lugano Hospital 58 IDH were detected by the automatic system of which 100% and 87,5% were predicted using 5 or 3 sessions respectively. A longer longitudinal dataset will allow a higher matching of J to actual IDH episodes. In conclusion, the evaluation of this new index at the beginning of the dialysis session prior to connecting the patient to the machine can provide the clinician with useful information about the risk for the patient to develop cardiovascular instabilities (IDH) during the treatment and can advise the physician about the need to modify the prescription.

Relationship between urea clearance and ionic dialysance determined using a single-step conductivity profile. Background On-line determination of ionic dialysance (ID) has been used to measure the clearance of small solutes like urea. However, attempts to determine the in vivo relationship between ID and urea clearance have led to discordant findings. The aim of this study was to determine the relationship between the mean values of repeated instantaneous determinations of ID throughout a dialysis session ( m ID), obtained using a single-step inlet dialysate conductivity profile, and the mean values of urea clearance corrected for access recirculation (K eu1 ), total recirculation (access plus cardiopulmonary recirculation, K eu2 ), and the entire postdialysis urea rebound (K wb ). Methods Eighty-two anuric patients on chronic thrice-weekly hemodialysis were studied using an Integra machine equipped with the Diascan module for the automatic determination of ID. The mean values of repeated ID measurements made at 30-minute intervals were compared with K eu1 (available for only 31 patients), K eu2 , and K wb . Results The results in all 82 patients were: m ID = 176 ± 23 mL/min; K eu2 = 181 ± 25 mL/min; K wb = 159 ± 22mL/min. The mean m ID/K wb and m ID/K eu2 ratios were, respectively, 1.11 ± 0.06 and 0.98 ± 0.06. The results in the 31 patients for whom K eu1 values were available were: m ID = 179 ± 24mL/min and K eu1 = 200 ± 27 mL/min; the mean m ID/K eu1 ratio was 0.90 ± 0.05. Conclusion The mean value of repeated ID determinations obtained using a single-step conductivity profile underestimates urea clearance corrected for access recirculation, and may be considered an adequate estimate of urea clearance corrected for total recirculation.

Every week, haemodialysis patients are exposed to approximately 400 l of water used for the production of dialysis fluids which, albeit with the interposition of a semi-permeable artificial membrane, come into direct contact with the bloodstream. It is therefore clearly important to know and monitor the chemical and microbiological purity of dialysis water.In this review, we analyse the sources of chemical and microbiological water contamination, and the problems involved in water purification systems and modalities. We also analyse the compliance of dialysis units with the microbiological standards established by the most widely accepted guidelines relating to the quality of dialysis fluids.The risk of chemical contamination is due mainly to the primary pollution of municipal water, whereas the most important microbiological problem is the control of bacterial growth in the water treatment and distribution system. Dialysis water treatment implies various levels of pre-treatment, a final purification module (which, in many cases, is reverse osmosis: RO) and a hydraulic circuit for the distribution of the purified water. RO-based treatment systems produce water of optimal chemical and microbial quality, and so dialysis units need to concentrate on maintaining this quality level in the long term by means of effective maintenance and disinfection strategies. The most widely accepted standards for water purity are those recommended by the Association for the Advancement of Medical Instrumentation and the European Pharmacopea, which respectively allow bacterial growth of200 and100 c.f.u./ml, and an endotoxin concentration of2 and0.25 IU/ml. However, a number of multicentre studies have reported that 7-35% of water samples have bacterial growth of200 c.f.u./ml, and up to 44% have endotoxin levels of5 IU/ml.The results of multicentre studies indicate that the microbial quality of dialysis fluids is still a too often neglected problem, particularly as there is evidence of a possible relationship between dialysis fluid contamination and long-term morbidity. The time has now come to take advantage of innovations in water treatment processes and improvements in dialysis machines in order to modify clinical practices and start improvement processes aimed at decreasing the risk of microbial contamination to the minimum, as it has already been successfully done in the case of chemical contamination.

How to determine ionic dialysance for the online assessment of delivered dialysis dose.BackgroundIonic dialysance may be equivalent to blood-water urea clearance corrected for recirculation (effective urea clearance); however, this is controversial. The aims of our study were (1) to verify in vivo whether the value of ionic dialysance is affected by the method of determination, given the effect of cardiopulmonary recirculation on inlet plasma water conductivity when the inlet dialysate conductivity is changed; and (2) to define the operative modalities for determining ionic dialysance to obtain an adequate estimate of effective urea clearance.MethodsThirty-three hemodialysis patients were studied during 186 dialysis sessions with low-flux polysulfone dialyzers using a modified Fresenius Medical Care 4008B machine equipped with meters to measure inlet and outlet dialysate conductivities. This machine varied inlet dialysate conductivity (Cdi) according to the following pattern: starting from baseline (step 0), Cdi was increased by 8% (step 1). After Cdi had reached the target value, which took 8 to 10 minutes, it was lowered to 8% below the baseline value (step 2). After 8 to 10 minutes, when Cdi had reached the new target, it was returned to its starting value (step 3). Four values of Conventional ionic dialysance (using the standard formula) and actual ionic dialysance (taking into account cardiopulmonary recirculation) were obtained for each cycle and were compared among them and with effective urea clearance (Kde).ResultsMean Conventional dialysance values at steps 0 to 2 and 2 to 3 (190 and 189mL/min) were similar and higher than those at steps 0 to 1 and 1 to 2 (171 and 181mL/min). Mean Conventional ionic dialysance values underestimated Kde, particularly at steps 0 to 1 (-22.2mL/min, P < 0.001) and 1 to 2 (-12.6mL/min, P < 0.001). The actual dialysance values underestimated Kde by no more than 4.3mL/min (P < 0.001). In steps 0 to 1 and 1 to 2, the underestimate of Kde by Conventional dialysance increased at higher values of Kde, but this relationship did not exist when considering actual dialysance.ConclusionsThe value of ionic dialysance is affected by the method of determination, given the effect of cardiopulmonary recirculation on inlet plasma water conductivity when inlet dialysate conductivity is changed. As a consequence, to provide a correct and direct estimate of effective urea clearance, ionic dialysance must be determined by changing inlet dialysate conductivity in such a way as to keep inlet plasma water conductivity constant by means of two symmetrical high and low dialysate conductivity steps.

Treatment of end-stage renal disease is a growing renal function. This should guarantee the same amount clinical, economic and organizational burden world- of depuration as was considered adequate before and wide, and consumes a large proportion of increasingly during the dietary treatment phase, although, in this scarce health care resources. case, the depuration comes from both residual renal Experimental studies and clinical data from uncon- function and dialysis clearance. trolled trials strongly suggest that a low protein diet may help to delay progression to chronic renal insuYciency (CRI ), but results of large-scale controlled Rationale of the integrated diet and dialysis

Despite technical and pharmacological improvements achieved over the past years, long-term prognosis of patients undergoing chronic hemodialysis is still rather poor. Cardiovascular disease is the leading cause of both morbidity and mortality in these patients, mostly because of their severely compromised cardiovascular conditions already at the time of starting hemodialysis. A proper management of factors involved in the development of cardiovascular abnormalities is therefore a basic pre-requisite for improving their clinical outcome. Hypertension and anemia should be adequately evaluated and corrected, in light of their primary involvement in the pathogenesis of left ventricular hypertrophy, whereas treatment of calcium and phosphate metabolism disorders, particularly of high serum phosphorus levels, is needed to prevent the development of severe secondary hyperparathyroidism and mainly vascular calcifications, whose detrimental pathophysiologic consequences on cardiovascular structures are huge. At the same time, the prescription of the hemodialytic treatment should be optimised, with a satisfactory removal of uremic toxins through the delivery of an adequate dialysis dose and with the use of biocompatible membranes, where possible, thus minimizing the inflammatory response secondary to the interaction between blood and the artificial material of the hemodialysis system. The clinical superiority of high-flux membranes, although suggested by all studies performed so far, has still to be demonstrated by well-conducted clinical studies; on-line convective treatments and daily hemodialysis, although promising, also need to be confirmed in randomized trials. In conclusion, long-term outcome of hemodialysis patients may only be improved by a complex, multi-factorial therapeutical approach.

Background. Data collected from registries provide a useful source of information for clinical practice. Therefore, several regional and national registries of end-stage renal disease (ESRD) patients have been established. The Lombardy Registry of Dialysis and Transplantation (RLDT) was established in 1982, with participation of all 44 dialysis units that were present at that time within the region. Methods. Demographic and clinical data on ESRD patients are collected yearly. We present here the results of some of the analyses that have been performed on RLDT data since it was started. Results. Briefly, data on epidemiology of ESRD, cardiovascular disease, patterns of care and patients’ outcomes have been considered. Comparisons with international registries have also been performed. Conclusions. This analysis shows how data collected from a homogeneous patient population receiving similar patterns of care provide precise information on that population. A clear example is provided by the similar results obtained in the comparison of highflux vs low-flux membranes in a randomized control trial, the HEMO study, and in an analysis of RLDT data. Therefore, analysis of data collected by registries represents an important tool to improve clinical practice and possibly patients’ outcomes.