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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.

Uremia is a systemic inflammatory condition characterized by a combination of oxidative burst, uremic toxicity, uremic dyslipidemia, endothelial dysfunction and oxidative stress resulting from dysf...

Lower limb ischemia affects the quality of life, physical activity and life expectancy of dialysis patients. The aim of this study was to investigate the risk factors associated with ischemic foot ulcers considering clinical, laboratory and therapeutic domains. This observational cohort study was based on data from the Nephrology and Dialysis Department database of Alessandro Manzoni Hospital, Lecco (Italy). All of the incident patients who started dialysis between 1 January 1999 and 29 February 2012 were enrolled, excluding temporary guests, patients with acute renal failure and patients with previous limb ischemia or amputation. Multivariate Cox regression analysis identified the predictors in each domain, which were matched in the final model. A time-dependent approach was used to take into account the evolution of some of the prognostic covariates. Of the 526 incident dialysis patients, 120 developed a lower limb ischemic lesion after a median of 13 months. The incidence of new ulcers was constant during the study period (6 per 100 person-years), but higher in the diabetics with a relative rate of 4.5. The variables significantly related to an increased risk of lower limb ulcers were age, male gender, diabetes, ischemic heart disease, treatment with proton pump inhibitors, iron, anticoagulants and calcium-based binders, and blood levels of phosphorus, triglycerides and C-reactive protein. The incidence of lower limb ulcers was highest during the early dialysis follow-up and was associated with, in addition to diabetes, modifiable laboratory and therapeutic predictors such as anticoagulants, proton pump inhibitors, calcium-containing binders, calcimimetics and iron.

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).

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 i...

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.

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.

The clinical benefits of on-line hemodiafiltration (HDF) versus high-flux membranes hemodialysis (hf-HD) are still debated. In fact, although a superiority of one treatment over the other, especially in terms of mortality, did not emerge from the analysis of clinical trials, improved intradialytic vascular stability and cardiovascular mortality have been observed in patients undergoing HDF rather than hf-HD; the lower removal of sodium (Na+) during HDF seems to play a major role. The plasma concentration of Na+ is the major determinant of plasma tonicity, which, by determining the flow of water between the intracellular and the extracellular compartment, contributes to the vascular refilling process and the maintenance of blood pressure during the hemodialysis treatment. Plasma tonicity also depends on plasma glucose concentration, especially in patients with diabetes mellitus with hyperglycaemia at the start of hemodialysis treatment. We evaluated the removal of Na+ and plasma tonicity balance during a 2-week period by performing 2–3 consecutive sessions of hf-HD followed by 2–3 consecutive sessions of HDF, or vice versa, in 47 patients (40% diabetics) on chronic hemodialysis. Identical parameters were used in all dialytic sessions. Na+ removal per session was − 224 ± 144 mmol and − 219 ± 152 mmol, respectively, in hf-HD and in HDF (p = 0.79). The plasma tonicity balance per session was − 575 ± 310 mOsm and − 563 ± 328 mOsm, respectively, in hf-HD and in HDF (p = 0.75). The removal of Na+ and plasma tonicity balance did not differ between hf-HD and HDF. This observation suggests that factors other than those assessed in our study might explain the improved cardiovascular stability reported in HDF.

Many observational studies have consistently shown that high-flux haemodialysis (hf-HD) has positive effects on the survival and morbidity of uraemic patients when compared with low-flux haemodialysis, and mainly considering the results of Membrane Permeability Outcome (MPO) studies there is evidence favouring high-flux treatments. A further improvement in convective treatments is represented by the on-line modality. On-line preparation from fresh dialysate by a cold-sterilizing filtration process is a cost-effective method of providing large volumes of infusion solution. Randomized, controlled, large-sized trials with long follow-up in haemofiltration (HF) are unfortunately lacking, possibly suggesting the difficulties in performing these trials, mainly in providing the same urea Kt/V considered adequate in HD. On-line haemodiafiltration (HDF) is considered the most efficient technique of using high-flux membranes, and clearances of small solutes like urea are higher in HDF than in HF and of middle solutes like β‎‎‎2-microglobulin are higher than in hf-HD. Thus HDF, as a strategy based on simultaneous diffusive and convective transport, may combine the beneficial effects of diffusive standard HD with the possible advantages of convective HF. Five large, randomized controlled trials just concluded are inconclusive in definitively clarifying the impact of on-line HDF on chronic kidney disease stage 5 patient outcomes.

Hyperphosphatemia is common in late stages of chronic kidney disease and is often associated with elevated parathormone levels, abnormal bone mineralization, extra-osseous calcification, and increased risk of cardiovascular events and death. Several classes of oral phosphate binders are available to help control plasma phosphorus levels. Although effective at lowering serum phosphorus, they all have safety, tolerability, and compliance issues that need to be considered when selecting which one to use.This paper reviews the most established treatment options for hyperphosphatemia, in patients with chronic kidney disease, focusing on the new inhibitors of active phosphate absorption.The prevention and the treatment of hyperphosphatemia is today far to be satisfactory. Nonetheless, an extending range of phosphate binders are now available. Aluminum has potentially serious toxic risks. Calcium-based binders are very effective but can lead to hypercalcemia and/or positive calcium balance and progression of cardiovascular calcification. No long-term data are available for the new calcium acetate/magnesium combination product. Lanthanum is an effective phosphate binder, and long-term effects of tissue deposition seem clinically irrelevant. Sevelamer, appear to have profiles that would lead to pleiotropic effects and reduced progression of vascular calcification, and the main adverse events seen with these agents are gastrointestinal. Iron has a powerful capability of binding phosphate, thus numerous preparations are available, both with and without significant systemic absorption of the iron component. The inhibitors of active intestinal phosphate transport, with their very selective mechanism of action and low pill burden seem the most interesting approach; however, do not seem at present to be effective alone, in reducing serum phosphorus levels.

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.

Hypertension is a well-known cardiovascular risk factor also for hemodialysis patients. Despite being common in this patient population, hypertension is often difficult to diagnose and poorly controlled.Blood pressure variability (BPV) is a new parameter and a predictor of poor outcomes in the general population. A recent observational study in over 11,000 hemodialysis patients showed that high BPV is associated with an increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. High BPV is associated with female gender, black race, obesity, diabetes and/or cardiovascular disease, hemoglobin levels less than 10 g/dL, high calcium-phosphate product, and use of three or more anti-hypertensive drugs.Today, the management of hypertension in hemodialysis patients requires more and more care, not only from the diagnostic point of view, but also in prognosis and therapy, especially regarding the non-pharmacological approach.

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are part of a spectrum of thrombotic microangiopathies. In the last years enormous progress has been made in understanding the pathogenesis of these entities. The fact that complement dysregulation is considered central in the development of atypical hemolytic uremic syndrome has led to the introduction of Eculizumab, a monoclonal anti-C5 inhibitor, in its treatment. These new advances have improved the outcomes in patients with atypical hemolytic uremic syndrome. Many unsolved issues remains, the most pressing ones being identifying the optimal treatment schedules and the underlying cause of the disease in patients without detectable complement mutations.

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.

Hyperphosphatemia is common in the late stages of chronic kidney disease (CKD) and is associated with elevated parathormone levels, abnormal bone mineralization, extraosseous calcification and increased risk of cardiovascular events and death. Several classes of oral phosphate binders are available to help control phosphorus levels. Although effective at lowering serum phosphorus, they all have safety issues that need to be considered when selecting which one to use.This paper reviews the use of phosphate binders in patients with CKD on dialysis, with a focus on safety and tolerability. In addition to the more established agents, a new resin-based phosphate binder, colestilan, is discussed.Optimal phosphate control is still an unmet need in CKD. Nonetheless, we now have an extending range of phosphate binders available. Aluminium has potentially serious toxic risks. Calcium-based binders are still very useful but can lead to hypercalcemia and/or positive calcium balance and cardiovascular calcification. No long-term data are available for the new calcium acetate/magnesium combination product. Lanthanum is an effective phosphate binder, but there is insufficient evidence about possible long-term effects of tissue deposition. The resin-based binders, colestilan and sevelamer, appear to have profiles that would lead to less vascular calcification, and the main adverse events seen with these agents are gastrointestinal effects.

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.

Encapsulating peritoneal sclerosis (EPS) is an uncommon but severe complication of peritoneal dialysis (PD). A reliable screening tool to identify patients at risk of developing or not EPS is currently not available. We aimed to evaluate whether the reduction in dialysate sodium concentration (sodium sieving) at 60 min (ΔDNa60), during a peritoneal equilibration test with 3.86% glucose concentration (3.86%-PET) was able to early rule out patients who will not develop EPS. Prospective controlled longitudinal (20-year) cohort study. All eligible incident PD patients attending the hospital underwent a 3.86%-PET during the first 3 months following start of PD and then once a year. The dip in ΔDNa60 and other factors were correlated with eventual EPS onset. Of 161 incident PD patients, with a median PD duration of 37.8 (24.7–58.3) months and 64.1 (34.5–108.3) months of follow-up, 13 patients (8%) developed EPS at a median PD duration of 72.7 (56.6–109.4) months and 105.0 (76.4–143.2) months of follow-up. ΔDNa60 demonstrated the best sensitivity and specificity values, estimated by conventional receiver operating characteristic (ROC) curve analysis with an area under the curve (AUC) of 0.90, 0.83 and 0.85 at 1, 2 and 3 years before the onset of EPS, respectively. Multifactorial analysis showed that the most useful factors for predicting EPS were age at start of PD, duration of PD, small solutes transport (D/PCreat) and ΔDNa60; the AUC at 1, 2 and 3 years before the onset of EPS was, respectively, 0.97, 0.96 and 0.94, the positive predictive value being 0.48, 0.57 and 0.42, and the negative predictive value 1.0, 1.0 and 1.0. It is possible to predict the occurrence and, better, the non-occurrence of EPS using simple parameters such as age at PD start, duration of PD, and parameters obtained by 3.86%-PET such as D/PCreat and ΔDNa60.

Background Dialysis is associated with a non-negligible rate of morbidity, requiring treatment customization. Many mathematical models have been developed describing solute kinetics during hemodialysis (HD) for an average uremic patient. The clinical need can be more adequately addressed by developing a patient-specific, multicompartmental model. Materials and Methods The data from 148 sessions (20 patients), recorded at the Regional Hospital of Lugano, Switzerland, were used to develop and validate the mathematical model. Diffusive and convective interactions among patient, dialysate and substitution fluid were considered. Three parameters, related to mass transfer efficiency at the cell membrane, at the dialyzer and at the capillary wall, were used to tune the model. The ability of the model to describe the clinical evolution of a specific HD session was evaluated by comparing model outputs with clinically acquired data on solutes and catabolite concentrations. Results The model developed in this study allows electrolyte and catabolite concentration trends during each HD session to be described. The errors obtained before the estimation of the patient-specific parameters drastically decrease after their identification. With the optimized model, plasmatic concentration trends can be described with an average percent error lower than 2.1% for Na+, CI-, Ca2+ and HCO3-, lower than 5% for K+ and lower than 8% for urea. Conclusions The peculiarity of the proposed model is the possibility it offers to perform a real-time simulation enabling quantitative appraisal of hematochemical quantities whose direct measurement is prohibitive. These will be beneficial to dialysis therapy planning, reducing intradialysis complications and improving patients’ quality of life.

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.

Purpose: Anemia in chronic kidney disease dialysis patients is a complex syndrome involving many causes. Adequate dialysis can contribute to its correction through many mechanisms, including the removal of molecules that may inhibit erythropoiesis. The aim of this pilot study was to evaluate the effect on renal anemia of two synthetic, high-flux dialyzers (polynephron vs. high-flux polysulphone). Methods: 20 dialysis patients (11 male; mean age: 72 years) were randomly assigned and studied for 6 months. There were 2 dropouts in each group. Each patient underwent 3 hemodialysis treatments per week without any difference in dialysis prescription. At T = 0 and T = 6 (after 6 months), instantaneous plasma clearances and reduction rates of small solutes, β2-microglobulin protein (β2-μ); hemoglobin (Hb), and iron pattern were measured. The effect on anemia was evaluated by calculating the Erythropoesis Stimulating Agent (ESA) doses and the Erythropoietin Resistance Index (ERI). Results: Kt/V increased between T0 and T6 in both groups. β2-μ pre-dialysis levels significantly decreased between T0 and T6 in both dialyzer groups (pConclusions: High-flux filters improved Hb levels, although only significantly in the polynephron group, suggesting a possible different effect. The results should be interpreted with caution and tested in an appropriately powered, large, prospective, randomized control trial.

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.