Predictors of haemoglobin levels and resistance to erythropoiesis-stimulating agents in patients treated with low-flux haemodialysis, haemofiltration and haemodiafiltration: results of a multicentre randomized and controlled trial.

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 eta(2) 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 eta(2) 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.

Molecular biology-based assessment of vitamin E-coated dialyzer effects on oxidative stress, inflammation, and vascular remodeling.

Cardiovascular disease represents the most common cause for the excess of morbidity and mortality found in end-stage renal disease (ESRD) and has prompted the exploration of multiple approaches to improve outcomes in these patients. Cardiovascular risk factors such as increased oxidative stress (OxSt) and inflammation are found in ESRD patients. A vitamin E-coated dialyzer using polysulfone membranes has been suggested to have positive effects on these factors. This 1-year study evaluated in 25 ESRD patients under chronic dialysis, the effects of a vitamin E-coated membrane (VitabranE ViE) "ex vivo" on mononuclear cells, OxSt, and inflammation-related biochemical and molecular biology markers using a molecular biology approach. p22(phox), heme oxygenase (HO)-1, plasminogen activator inhibitor (PAI)-1 protein level, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 status were evaluated at the beginning of the study, after 6 months and after 12 months by Western blot analysis and oxidized low-density lipoprotein (OxLDL) plasma level by enzyme-linked immunosorbent assay, alongside vascular remodeling assessment as measured by carotid intima-media thickness (IMT) in a subgroup of nine randomly selected patients. p22(phox), PAI-1, OxLDL, and pERK all decreased with VitabranE use, while HO-1 increased. Carotid IMT did not increase. Treatment with VitabranE significantly decreases the expression of proteins and markers relevant to OxSt and inflammation tightly associated with cardiovascular disease, and it appears highly likely that VitabranE use will provide a benefit in terms of cardiovascular protection.

Extended dosing of darbepoetin alfa in peritoneal dialysis patients.

BACKGROUND: Anemia is common among peritoneal dialysis (PD) patients, and most patients require erythropoiesis-stimulating agents (ESA) to maintain their hemoglobin concentrations within current guideline recommendations. Darbepoetin alfa is an ESA with a 3-fold longer half-life and greater in vivo biological activity than recombinant human erythropoietin, allowing less frequent dosing that may simplify anemia management in these patients, providing benefits to patients, care givers and health care providers. Clinical studies have confirmed the efficacy and safety of darbepoetin alfa administered at extended dosing intervals. However, there are limited data on the management of anemia with ESAs in PD patients in routine clinical practice. The aim of this multicenter observational study in European and Australian dialysis patients was to evaluate darbepoetin alfa administered once every 2 weeks (Q2W) in routine clinical practice for 12 months. METHODS: PD patients ≥18 years old and converting to treatment with darbepoetin alfa Q2W were eligible for enrollment regardless of previous or current ESA use. Patients enrolled in the study were treated according to local usual clinical practice. Data were collected up to 6 months prior to and 12 months after conversion to darbepoetin alfa Q2W. The primary endpoint was hemoglobin concentration 12 months after conversion to darbepoetin alfa Q2W. RESULTS: Of the 741 eligible PD patients (mean age, 61 years; male, 57%), 640 (86%) completed the study. Mean hemoglobin concentration (g/dL) was 11.69 (95% CI, 11.53-11.86) 6 months before the conversion, 12.25 (95% CI, 12.13-12.38) at conversion, and 11.88 (95% CI, 11.74-12.02) 12 months after conversion to darbepoetin alfa Q2W. The weekly equivalent ESA dose (µg/wk) was a geometric mean of 25.24 (95% CI, 23.46-27.15) 6 months before conversion, 20.90 (95% CI, 19.13-22.83) immediately before conversion, 18.89 (95% CI, 18.13-19.68) at conversion and 19.04 (95% CI, 17.69-20.49) 12 months after conversion. Twelve months after conversion, 70% of patients were receiving darbepoetin alfa Q2W and 73% had hemoglobin concentrations >11.0 g/dL. CONCLUSION: In this large observational study, PD patients were able to maintain mean hemoglobin concentrations >11.0 g/dL after conversion to extended dosing of darbepoetin alfa Q2W, with no mean dose increase.

Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD.

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

Peritoneal Equilibration Test Reference Values Using a 3.86% Glucose Solution During the First Year of Peritoneal Dialysis: Results of a Multicenter Study of a Large Patient Population.

BACKGROUND: The original peritoneal equilibration test (PET) was used to classify peritoneal dialysis (PD) patients using a 2.27% glucose solution. It has since been suggested that a 3.86% glucose solution be used because this provides better information about ultrafiltration (UF) capacity and the sodium (Na) sieving of the peritoneal membrane. OBJECTIVE: The aim of this study was to determine reference values for a PET using a 3.86% glucose solution (PET-3.86%). METHODS: We evaluated the PET-3.86% in a large population of incident PD patients attending 27 Italian dialysis centers. RESULTS: We evaluated the results of 758 PET-3.86% in 758 incident PD patients (1 test per patient). The mean duration of PD was 5 ± 3 months. The ratio of the concentrations of creatinine in dialysate/plasma (D/PCreat) was 0.73 ± 0.1 (median 0.74). The ratio between the concentrations of glucose at the end/beginning of the test (D/D0) was 0.25 ± 0.08 (median 0.24). Ultrafiltration uncorrected and corrected for bag overfill was respectively 776 ± 295 mL (median 781 mL) and 675 ± 308 mL (median 689 mL). Sodium sieving was 8.4 ± 3.8 mmol/L (median 8.0 mmol/L). CONCLUSION: The results of the study provide PET-3.86% reference values for the beginning of PD that can be used to classify PD patients into transport classes and monitor them over time.

Effect of balance Solution on the Peritoneal Membrane in Automated Peritoneal Dialysis.

Interference of conventional peritoneal dialysis fluids (cPDFs) with peritoneal membrane cell functions may be attributed to the dialysis fluid's low pH, high glucose concentration, and/or the presence of glucose degradation products (GDPs), the last of which leads to higher levels of advanced glycation end-products (AGEs). It has been suggested that the peritoneal membrane might be better preserved by using biocompatible solutions, including cancer antigetn 125 (CA125). This prospective, open-label, multicentre, randomized, controlled, cross-over phase IV study compared the in vivo biocompatibility of a neutral-pH, low-GDP peritoneal dialysis (PD) solution (balance) with a cPDF in automated PD (APD) patients. Our study revealed a significantly increased appearance rate and concentration of CA125 in the peritoneal effluent of APD patients treated with the neutral-pH, low-GDP solution balance versus a conventional PD solution.

Incidence of renal replacement therapy in Veneto for 2008, 2009 and 2010.

This section of the report of the Veneto Dialysis and Transplantation Registry (VDTR) provides data on the incidence of patients receiving renal replacement therapy (RRT) in the region from 2008 to 2010. Its purpose is to provide health authorities with the information they need to plan the delivery of RRT in Veneto. Data were obtained from the VDTR, defining incident patients according to the recommendations of the Italian Dialysis and Transplantation Registry. The incidence rate was calculated per million population (pmp). Variability by province and treatment center was studied by applying multilevel modeling methods. An age-period-cohort model was used to forecast the incidence rate of RRT over the years to come. The incidence of patients on RRT was 114.23 pmp in 2008, 120.15 pmp in 2009 and 107.08 pmp in 2010. The patients' median age at the time of starting RRT was 70.5 in 2008, 68.7 in 2009 and 69.5 in 2010. During these 3 years, 66.3% of patients were male, and 33.7% were female. Incidence rates were not uniformly distributed between the provinces in the region, but were significantly higher in 2. The incidence rate of patients needing RRT seems likely to remain stable in the future, until 2015 at least. Renal vascular disease was the primary cause of end-stage renal disease (ESRD), followed closely by diabetes, while the proportion due to primary glomerulonephritis has gradually decreased. Initial dialysis modality was hemodialysis (HD) for 78% of patients, while about 20% started RRT on peritoneal dialysis (PD), and a negligible proportion had a preemptive kidney transplantation. About 35% patients began dialysis with a temporary vascular catheter; this percentage remained fairly constant until 2010. The incidence of RRT in Veneto is one of the lowest in Italy and remained substantially stable over the period 1998-2010, despite the population of patients with ESRD becoming older and more severely ill. This finding could mean a heavier burden on the welfare system in the future.

Prevalence of renal replacement therapy in Veneto for 2008, 2009 and 2010.

The aim of this section is to provide descriptive data for end-stage renal disease (ESRD) in the Veneto Region (Italy). Data were obtained from the Veneto Dialysis and Transplantation Registry (VDTR). Patients were considered to be prevalent renal replacement therapy (RRT) patients if alive on 31 December of each year examined. Prevalence is expressed per million population (pmp). The trend for prevalence of each treatment in the period examined was estimated by random effects longitudinal logistic regression. Prevalence of RRT in Veneto in the years 2008, 2009 and 2010 was 888, 923 and 950 pmp, respectively. The prevalence of RRT patients by treatment modality showed a slight increase for hemodialysis, notable stability for peritoneal dialysis and a more pronounced increase for transplantation. Every year, about 10% of peritoneal dialysis patients shifted to hemodialysis, and 12% received a transplant. The transition probability from hemodialysis to peritoneal dialysis was negligible, and less than 5% of hemodialysis patients received a transplant. The probability of returning to hemodialysis after having received a transplant was less than 2% a year. Bicarbonate hemodialysis slowly increased from 1998 to 2010, both in percentage and in prevalence per million population; conversely, hemodiafiltration (HDF) showed a mild but constant decrease. Automated peritoneal dialysis (APD), which was quantitatively almost negligible in 1998, reached the same level as continuous ambulatory peritoneal dialysis (CAPD) in 2010. The prevalence of patients undergoing living donor transplants almost doubled in the period 1998-2010. The increase of prevalence over time was not proportional for the 3 modalities of RRT: hemodialysis prevalence grew slowly, peritoneal dialysis prevalence remained stable, and renal transplant prevalence quickly increased.

Mortality in the Veneto population on renal replacement therapy.

This section reports survival rates for patients on renal replacement therapy (RRT). The data obtained from the Veneto Dialysis and Transplantation Registry (VDTR) cover the whole population in the region. Patients on RRT alive on 31 December of each year were assumed to be at risk of dying in the following year. Furthermore, time-to-event analysis was used to describe the complete history of patients from when they started RRT until they died, including transitions between the 3 main treatment modalities - hemodialysis (HD), peritoneal dialysis (PD) and renal transplantation. The cohort of patients starting RRT from 1998 to 2010 was followed up until 31 December 2010. Survival rates from the first treatment to death were calculated according to the life table method. Relative survival and excess mortality rates were estimated according to the Ederer II method. A multistate model was used to describe changes in a patient's condition (changes of treatment, or death) over time. Among prevalent patients on RRT, the annual risk of death was 10.65% in 2008, 9.35% in 2009 and 8.86% in 2010. The overall mortality rate was 12.5 per 100 patient-years (95% confidence interval [95% CI], 12.1-13.0). The 5-year relative survival was 59% (95% CI, 57%-60%), and at 10 years relative survival was 41% (95% CI, 39%-43%); the estimated excess mortality rate was very high at the start of RRT (18 per 100 patient-years) but gradually decreased after the second year. On multivariate analysis, excess mortality was associated with age and primary renal diseases. Less than 10% of patients starting on PD shifted to HD in the first year of RRT, and a considerable proportion received a transplant, amounting to 6% in the first year, and thereafter increasing steadily: at the end of the fifth year, 34% of patients starting RRT on PD had received a transplant. HD patients behaved differently: any shift to PD was negligible, and the patients receiving a transplant amounted to only 2% in the first year and about 16% by the end of the fifth year. Cumulative mortality among HD patients was particularly high (already 18% at 1 year, and 70% at 10 years) by comparison with those on PD (8% at 1 year, 54% at 10 years). Although mortality on RRT is not particularly high in Veneto by comparison with countries other than Italy, this result is mainly due to an increasing number of patients receiving transplants, which makes them a favorably selected population. The mortality rate was high among those on HD, particularly in the first year. Our population on RRT is rather heterogeneous, and a description of the outcomes based only on the whole population may be misleading.

Peritoneal ultrafiltration in patients with advanced decompensated heart failure.

The aim of the Best Practice guidelines on peritoneal ultrafiltration (UF) in patients with treatment-resistant advanced decompensated heart failure (TR-AHDF) is to achieve a common approach to the management of decompensated heart failure in those situations in which all conventional treatment options have been unsuccessful, and to stimulate a closer cooperation between nephrologists and cardiologists. The standardization of the case series of different centers would allow a better definition of the results published in the literature, without which they are nothing more than anecdotes. TR-AHDF is characterized by the persistence of severe symptoms even when all possible pharmacological and surgical options have been exhausted. These patients are often treated with methods that allow extracorporeal UF - slow continuous ultrafiltration (SCUF) and continuous renal replacement therapy (CRRT) - which have to be performed in hospital facilities. Peritoneal ultrafiltration (PUF) can be considered a treatment option in patients with TR-AHDF when, despite the fact that all treatment options have been used, patients meet the following criteria: • stage D decompensated heart failure (ACC/AHA classification); • INTERMACS level 4 decompensated heart failure; • INTERMACS frequent flyer profile; • chronic renal failure (estimated glomerular filtration rate <50 ml/min per 1.73 m2: KDOQI classification stage 3 chronic kidney disease); • no obvious contraindications to peritoneal UF. PUF treatment modes are derived from the treatment regimens proposed by various authors to obtain systemic UF in patients with severe decompensated heart failure, using manual and automated incremental peritoneal dialysis involving various glucose concentrations in addition to the single icodextrin exchange. These guidelines also identify a minimum set of tests and procedures for the follow-up phase, to be supplemented, according to the center's resources and policy, with other tests that are less routine or more complex also from a logistic/organizational standpoint, emphasizing the need for the patient's clinical and treatment program to involve both the nephrologist and the cardiologist. The pathophysiological aspects of a deterioration in kidney function in patients with decompensated heart failure are also considered, and the results of PUF in patients with decompensated heart failure reported in the various case series are reviewed.

[Peritonitis and catheter-related infections in peritoneal dialysis]. / La peritonite e le infezioni del catetere in dialisi peritoneale.

The incidence of peritoneal dialysis-related infections has decreased markedly over the past 20 years. This is commonly believed to be the result of improvements in connection technology and eradication of nasal and exit-site Staphylococcus aureus. However, peritonitis is still the most important cause of technique failure. The good results of single centers with a long experience of peritoneal dialysis and the excellent randomized trial results have proved to be incomparable with those of nonselected populations. The analysis of organism-specific infections joined to the identification of the entry pathway into the peritoneum could allow individual centers to focus on the weaknesses of the used protocols and procedures.

Twenty years of bicarbonate solutions.

For many years, lactate has been used successfully as a buffer in peritoneal dialysis solutions although its effectiveness in the correction of uremic acidosis and its biocompatibility on peritoneal resident cells have been questioned. In addition, some investigators have suggested other potential adverse metabolic effects resulting from the unphysiologically high lactate flux into the body during CAPD. These potential problems associated with lactate-containing CAPD solution prompted the search for alternative buffer-containing solutions. Bicarbonate, the physiological buffer, was considered when the problem of calcium and magnesium carbonate solubility was solved by the use of a two-compartment bag system allowing the mixing of bicarbonate and divalent cations immediately before infusion. The long-term tolerance, safety, efficacy and therapeutic value of a bicarbonate-buffered peritoneal dialysis solution have been evaluated for about 15 years. RCT studies demonstrated a benefit for acid base improvement, while observational reports showed other clinical effects such as a preservation of residual renal function, less inflammatory effect and peritonitis prevention. In addition, there is a consensus that local biocompatibility is improved. Therefore, as bicarbonate is the physiological buffer of the body, it should become the solution of choice in PD patients.

Tailoring peritoneal dialysis fluid for optimal acid-base targets.

Mild derangements of acid-base status are common features in peritoneal dialysis patients, metabolic acidosis being the most frequent alteration. One of the main tasks of dialysis is to correct these derangements and the target is the normalization of the acid-base parameters since they affect several organs and functions. Since factors affecting acid-base homeostasis are intrinsic characteristics of the individual patient (metabolic acid production, distribution space for bicarbonate, dialytic prescription, etc.), it is not surprising that only relatively few patients achieve the normal range. Only a certain modulation of buffer infusion by using different buffer concentrations in the dialysis fluid may ensure a good correction in a large percentage of patients.

Acid-base homeostasis with the high convective dialysis treatments.

The feedback between metabolic acid production and dialytic base gain ensures a neutral acid-base balance in patients on renal replacement therapy (RRT). Despite acid not accumulating continuously, clinical studies demonstrated that normalizing pre-dialysis serum bicarbonate results in nutritional and osteodystrophy improvements. Full correction of acidosis is not an easy task in dialysis patients because it depends on both some intrinsic characteristics of patients and dialysis prescriptions. Thus, a large variation in the result is often recorded among dialysis populations and in acid-base studies. Highly convective dialysis treatments make the individualization of dialytic parameters easier than conventional dialysis. Up to now, few clinical data have been published. However, knowledge of and the quantification of the kinetic phenomena that govern the buffer transfer during a session of these high performance treatments can provide a rational approach to the optimal dialysis prescription.

Individualized bicarbonate concentrations in the peritoneal dialysis fluid to optimize acid-base status in CAPD patients.

BACKGROUND: A large percentage of peritoneal dialysis (PD) patients being treated with standard lactate-containing solutions tend to have serum bicarbonate concentrations below or above the normal range. The inter-patient variability of serum bicarbonate is a result of many influences and it may be appropriate to adjust the bicarbonate concentration in the peritoneal dialysis fluid (PDF) to the current serum bicarbonate in the individual patient. METHODS: Two concentrations of bicarbonate in PDF were compared in this study (34 and 39 mmol/l). Eligible patients underwent a pre-study phase of 12 weeks to determine serum bicarbonate every six weeks. Sixty-one patients entered the stratification phase. Acidotic patients (serum venous bicarbonate <25.3 mmol/l) were allocated to the high bicarbonate solution, patients in the normal serum bicarbonate range or alkalotic patients (serum venous bicarbonate >25.3 mmol/l) to the low bicarbonate solution. Patients were followed up for 24 weeks, in which study visits were performed every 6 weeks to assess acid-base status, peritoneal and renal function, and to calculate protein nitrogen appearance rate (PNA). RESULTS: Patients with acidosis at baseline had higher body weight, body surface area, blood urea nitrogen, serum creatinine and PNA than patients with bicarbonate within the normal range or with alkalosis. They significantly improved their serum bicarbonate (23.45 +/- 2.5 vs 25.7 +/- 2.8 mmol/l, baseline vs week 24; P < 0.01), whereas patients treated with the low bicarbonate PDF maintained their serum venous bicarbonate over the 24 week study period (27.77 +/- 2.9 vs 27.06 +/- 2.1 mmol/l, baseline vs week 24; P = NS). Analysing both study groups together, at baseline, 66% of the patients presented with mild to moderate acidosis, this figure at the end of the study was 23.4%. PNA did not change in the two groups; however, in the subgroup of patients (N = 23) in whom the 39 mmol/l PDF was effective in correcting metabolic acidosis, a decrease in PNA was observed. CONCLUSIONS: The study demonstrated that the individualized application of low and high bicarbonate PD PDFs allows one to achieve normal acid-base status in a large percentage of CAPD patients with potential benefits to nutritional status.

Convection versus diffusion in dialysis: an Italian prospective multicentre study.

The concept of dialysis adequacy has to be widened to include medium size and large molecule removal in addition to urea kinetics. The HEMO study found a non-significant trend toward a beneficial effect on mortality of high-flux dialysis compared with low-flux dialysis. In that study, the beneficial effect of convection could have been attenuated by the fact that 'internal filtration' in high-flux haemodialysis (HD) is lower than that expected by convection in haemofiltration (HF) or haemodiafiltration (HDF). To explore the putative beneficial effect of convection, this Italian multicentre study was planned, comparing on-line convective treatments (HF and HDF) with standard, low-flux HD. The enrolled patients will be evaluated prospectively on their usual treatment for 2 months (baseline period) and subsequently randomized to continue either with low-flux HD (50%) or to start on-line convective treatment (50%), HF or HDF according to a 1:1 ratio. The primary end point of the study will be cardiovascular stability and blood pressure control. As secondary aims of the study, the impact on symptoms, morbidity and mortality will be assessed. Feasibility and patient compliance during HF and HDF treatments will also be evaluated. The experimental phase of the study, of at least 2 years, is divided into a 3-month adaptation period and a subsequent evaluation period. A recruitment period of 1 year is planned. The study design has adequate power to detect an absolute reduction of 3% hypotensive episodes with the experimental convective treatments compared with standard low-flux HD.