BACKGROUND:Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested.METHODS:We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).

T. Akiba, Tokyo R. Amerling, New York, N.Y. A. Al-Khader, Riyad W. Arkouche, Lyon S. Ash, West Lafayette, Ind. B.J.-M. Canaud, Montpellier C. Chazot, Tassin A.K. Cheung, Salt Lake City, Utah W. Clark, Indianapolis, Ind. J.T. Daugirdas, Chicago, Ill. S. Di Giulio, Rome D. Falkenhagen, Krems K. Farrington, Stevenage L. Garred, Thunder Bay, Ont. N. Gibney, Edmonton, Alta. T. Goodship, Newcastle upon Tyne M. Haapio, Helsinki O. Heimbürger, Stockholm

Background: Hemofiltrate reinfusion (HFR) is a form of hemodiafiltration (HDF) in which replacement fluid is constituted by ultrafiltrate from the patient ‘regenerated’ through a cartridge containing hydrophobic styrene resin. Bicarbonate-based dialysis solutions (DS) used in routine hemodialysis and HDF contain small quantities of acetate (3–5 mM) as a stabilizing agent, one of the major causes of intradialytic hypotension. Acetate-free (AF) DS have recently been made available, substituting acetate with hydrochloric acid. The impact of AF DS during HFR on Hb levels and erythropoietic-stimulating agent (ESA) requirement in chronic dialysis patients was assessed. Patients and Methods: After obtaining informed consent, 30 uremic patients treated by standard bicarbonate dialysis (BHD, DS with acetate) were randomized to treatment in 3-month cycles: first AF HFR, followed by HFR with acetate, and again AF HFR. At the beginning and end of each period, Hb and ESA requirements were evaluated. Results: A significant increase in the Hb level was observed throughout all periods of HFR versus BHD (from 11.1 to 11.86 g/dl; p = 0.04), with a significant decrease of ESA requirements from 29,500 to 25,033 IU/month (p = 0.04). Conclusion: Regardless of the presence or absence of acetate in DS, HFR per se allows a significant lowering of ESA dosage versus BHD, while at the same time increasing Hb levels. Taking for granted the clinical impact produced, HFR seems to provide a relevant decrease in end-stage renal disease patient costs.

Aim: The purpose of this study was to optimize the operative and analytical methodologies to a more exact determination of intradialytic kinetics of the phosphates (P) tested in hemodialysis (HD) and in on-line hemodiafiltration with endogenous reinfusion (HFR – Hemo Filtrate Reinfusion). Methods: The mass balance measurements of urea and P were carried out in 18 clinically stable HD patients. The effective blood flow (Qb) was measured with a Transonic® monitor. The plasma was deproteinized with 10% trichloroacetic acid to prevent breakdown of the proteins and the consequent pseudohyperphosphatemia. Subsequently the supernatant containing the ultrafiltrable phosphates was made to react with a solution of ammonium molybdate for a spectrophotometric reading. Results: The mean urea mass transfer in HD was 16.9 g/session and in HFR 15.4 g/session. The mean P mass transfer in HD was 726 mg/session and in HFR 679 mg/session. Nevertheless, in HFR a significant difference was verified between the clearances of P, between the plasma water side (122.4 ± 30.8 ml/min) and the dialysate side (105.9 ± 19.4 ml/min). Conclusion: As far as the P mass transfer is concerned, the data obtained is able to be superimposed with that described in the literature during HD, while in HFR it is possible to hypothesize a high efficiency, thanks to an increased output of P in relation to the phenomenon of adsorption which, although is limited, contributes to the transfer of the total mass. Based on this study and re-examining the literature on P kinetics, there is space for methodological improvement both on the operating front with careful determination of the effective Qb, and on the chemical front overcoming the inaccuracy of automatic analyzers in determining the plasma P owing to possible overestimation of phosphatemia and poor sensitivity in measuring the lower levels of P present in the dialysate and/or ultrafiltrate.

Aim The purpose of the study was to examine the effect of hemodiafiltration with endogenous reinfusion (HFR) compared to hemodialysis (HD) on 28 uremic patients with secondary hyperparathyroidism (2HPT) but positively selected for good and stable control of phosphatemia in order to evaluate the independent effects of dialysis treatments on bone turnover metabolism. Methods: The study was divided into 3 periods of observation: a) HD for three months; b) HFR for three months; c) HFR for a further 3 months. We analysed the trend of: whole PTH, 1–84 PTH, 7–84 PTH, alkaline phosphatase and its bone isoenzyme, total and ionised calcium, phosphatemia, dose of phosphate binder agents, β2-microglobulin, CRP. All the variations found were evaluated through mean values ± SD, t-tests, multivariate analysis. Results We observed a deceleration in bone turnover characterized by a reduction of the total and bone alkaline phosphatase (IU/mL) from 92.3 ± 82.8 and 35.8 ± 49.8 at the end of HD to 63.4 ± 23.9 and 16.0 ± 8.7 at the end of HFR, respectively, and 1–84 PTH from 317.5 ± 264.6 pg/mL at the end of HD to 287.5 ± 258.9 pg/mL at the end of the 3rd month of HFR. β2-microglobulin was reduced from 32.9 ± 16.1 mg/L at the end of HD to 26.4 ± 8.1 mg/L already at the end of the first three months of HFR. CRP was reduced from 2.5 ± 2.6 mg/dL at the beginning of the study to 1.3 ± 1.7 mg/dL at the end of HFR. There were no differences with regard to: dialytic efficiency, nutritional status, calcemia, phosphatemia (maintained in the K-DOQI range for the entire duration of the study), also thanks to more careful use of phosphate chelating agents. Conclusion We are of the opinion that HFR - essentially thanks to the use of ultrapure endogenous infusate - induces a deceleration in bone turnover due to 2PHT. In addition, phosphate substraction in HFR is better compared to HD, thanks to the improvement of the anti-inflammatory conditions by removing the cytokines harmful to bone metabolism and excluding a priori the negative effects related to hyperphosphatemia. (Int J Artif Organs 2006; 29: 1042–52)

Background. Alport syndrome (AS) is a hereditary disease of the glomerular basement membrane in the kidney characterized by progressive renal failure, sensorineural deafness. and/or ocular abnormalities. In contrast to the well-known X-linked phenotype, very little is known about the autosomal dominant form. Rare autosomal forms of AS have been described with mutations in COL4A3 and COL4A4 at chromosome region 2q35-q37, but there have been no descriptions of dominant forms due to a mutation in COL4A4.Methods. We describe a Sardinian family with a classical AS-phenotype plus hypercholesterolaemia, a clinical feature also present in Fechtner syndrome (FS), a disease that segregates as an autosomal dominant trait.Results. A suggestive linkage (LOD= 2.7) between AS and the COL4A3/A4 locus at 2q35-q37 was identified. Other candidate collagen genes encoding basement membrane collagen (COL4A1/A2 and COL4A5/A6) were excluded by linkage analysis (13q33-q34 and Xq22), or by sequence (COL4A3). DNA sequence analysis of the COL4A4 gene revealed that the Lys325Asn mutation was present in all affected family members, but was absent in all unaffected members and in a random sample of the Sardinian population. A clear indication of a gene-dosage effect was seen in the most severely affected family member, since she carried the mutation in the homozygous form.Conclusions. These data confirm the importance of collagen 4A4 as a component in the structural integrity of the glomerular basement membrane and confirm the phenotypic and genetic heterogeneity of collagen disorders.

BACKGROUND:The potential superiority of various renal replacement treatment modalities consisting largely of convective mass transfer as opposed to primarily diffusive mass transfer, is still a matter of debate. The objective of the present study was to evaluate acute and long-term clinical effects of varying degrees of convection and diffusion in a group of 24 clinically stable patients with end-stage renal disease.METHODS:The patients were prospectively assigned to three consecutive treatment schedules of 6 months each: phase I (HF1) (on-line predilution haemofiltration)-->phase II (HD) (high-flux haemodialysis)-->phase III (HF2; as phase I). We used the AK100/200 ULTRA monitor (Gambro), which prepares ultrapure dialysis fluid for HD and sterile, pyrogen-free substitution solution for HF. The membrane (polyamide), fluid composition, and treatment time were the same on HF and HD. The targeted equilibrated Kt/V was 1.2 for both treatment modes, creating a similar urea clearance.RESULTS:Fifteen patients, mean age 62.8+/-8.4 years, completed the study according to the above conditions. Urea kinetics, nutritional parameters, and dry weight were similar in the three periods. The frequency of intra-treatment episodes of hypotension/patient/month was significantly lower on HF1 (1.24) and HF2 (1.27) than on HD (1.80) (P<0.04). It decreased progressively on HF1, then increased on HD, and decreased again during HF2. Patients had fewer muscular cramps on HF than on HD (P<0.03) and required significantly less saline and plasma expander during HF than HD sessions. The prevalence of inter-treatment symptoms, including fatigue and hypotension, was lower on HF than on HD (score difference P=0.04). Quality of life, determined by the Laupacis method in all three periods, showed a tendency towards improvement during the study, reaching the best values during HF2.CONCLUSIONS:HF has a progressive stabilizing haemodynamic effect, producing a more physiological cardiovascular profile than HD. This long-term effect, observed in stable patients treated under strictly identical conditions, is probably due to the mechanism of convection, and is different from the acute effect observed mainly in unstable patients.

Sardinian Collaborative on Haemofiltration On-Line Gambro,

The aims of the present prospective multicenter study were to assess the clinical tolerance and well being, the correlation between nPCr and Kt/V and the pretreatment beta(2)-microglobulin level in patients sequentially treated with high-flux dialysis with ultrapure bicarbonate hemodialysis (HD; phase I) and predilution hemofiltration (HF) with on-line prepared bicarbonate substitution fluid (phase II). The same monitor (Gambro AK 100 ULTRA(R)) and membrane (polyamide) were used. Twenty-three patients, all in a stable clinical condition, entered the study. The treatment was targeted to an equilibrated Kt/V (eqKt/V) of 1.4 for HD and 1.0 for HF. No mortality or relevant morbidity were observed. The number of hypotensive episodes was 1.78 +/- 2.8 per patient and month during HD vs. 1.17 +/- 3.1 during HF (p = 0.003) and the number of the hypertensive episodes 1.28 +/- 2.8 during HD vs. 0.42 +/- 0.8 during HF (p = 0.04). Incidences of arrhythmia, muscular cramps and headache were significantly less frequent during HF. Interdialytic cramps, arthralgia and fatigue were also significantly less frequent during the HF period. The average beta(2)-microglobulin level was 27.1 +/- 14.7 mg/dl at the start of the study, 22.9 +/- 4.9 mg/dl at the beginning of phase II and 22.4 +/- 4 mg/dl at the end of phase II (p = 0.01 compared to the start). A significant linear correlation between the normalized protein catabolic rate and eqKt/V was obtained faster during HD than during HF (45 vs. 120 days) indicating that HF affects the nutritional status with mechanisms different from HD. The present study is in agreement with the hypothesis that HF gives an adequate nutritional status with improved clinical stability and well being at a lower Kt/V compared to HD. Both therapies were efficient in controlling the pretreatment beta(2)-microglobulin level.