Hemodiafiltration with endogenous reinfusion with and without acetate-free dialysis solutions: effect on ESA requirement.

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.

Effect of on-line hemodiafiltration with endogenous reinfusion (HFR) on the calcium-phosphorus metabolism: medium-term effects.

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, beta2-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. Beta2-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 subtraction 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.

New method for phosphate kinetics estimation during hemodialysis and on-line hemodiafiltration with endogenous reinfusion.

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.

[Hemodiafiltration with endogenous reinfusion (HFR): evolution of the method]. / Emodiafiltrazione con reinfusione endogena (HFR): evoluzione della metodica.

During hemodiafiltration (HDF) the increase in the ultrafiltration (uf) rate improves solute convective clearance. Therefore, considerable amounts of reinfusion liquid are necessary, whose quality must be guaranteed. The use of bags or bottles manufactured by industry causes many problems concerning handling (storage, repeated connections) and costs, and last but not least, it exposes the circuits to a contamination risk. Therefore, the technological research into on-line production systems of sterile and ultrapure reinfusion solutions is justified. The increasing interest in the on-line production of reinfusion fluids from the dialysing solution dates back to the 1990s, and the data in the literature are statistically positive concerning the improvement in depurative performances connected to the uf increase. Although, to be objective, a problem still exists, in real-time the absolute guarantee of the sterility and apirogenicity of the solutions produced on-line is impossible. Using a two-chamber filter, it is possible to produce reinfusion fluid from the uf of the patient himself, which has been 'regenerated' by a sorbent bed, in a closed circuit. This action eliminates any sterility problems, whilst, in addition, providing the possibility for good substance reinfusion such bicarbonates and essential and branched-chain aminoacids. This HDF method, hemo-filtrate-reinfusion (HFR), has clinically demonstrated, beyond its ease of execution, a reduction in physiological component loss, a high biocompatibility and an overall action in contrast to MIA syndrome factors, i.e. malnutrition, inflammation and atherosclerosis.

Hemodiafiltration with post-dilution reinfusion of the regenerated ultrafiltrate: a new on-line technique.

AIMS: All convective hemodiafiltration techniques require a replacement fluid, which must have an adequate electrolytic composition and must be sterile and pyrogen-free. Using an integrated adsorption cartridge, the ultrafiltrate can be "regenerated" and used as a replacement fluid (hemo-filtrate reinfusion; HFR). The aim of this study was to evaluate whether the HFR technique as suggested in its original configuration could be improved by inverting the purification sequence (post-dilution HFR; PDHFR) in order to increase the purification efficiency of the whole system. METHODS: We performed standard HFR in 6 uremic patients during 6 months and, subsequently, during further 6 months, PDHFR. The dialytic efficacy of the two techniques and the filter blood loss were evaluated. Moreover, we studied how both techniques affected cytokine levels. RESULTS: We observed a significant increase of urea extraction and of Kt/V values in PDHFR. An equally significant improvement was observed in regard to the extraction of beta2-m and the blood loss. Furthermore, IL6 and TNFalpha decreased significantly after PDHFR treatment. CONCLUSIONS: HFR has proven to be an easy-to-perform hemodiafiltration technique, capable of resolving the typical problem of the other hemodiafiltration technique, the availability and production of a sterile and ultrapure reinfusion solution. The inversion of its configuration has allowed us to improve three aspects that have characterized, in our experience, the treatments performed in the original geometry: the removal of both urea and beta2-m, and the filter. Finally, it's notable that the decrease in cytokines levels achieved with PDHFR might attenuate the uremic micro-inflammatory state.

[Contact phase activation can occur with certain types of activated carbon]. / Attivazione della fase contatto, durante emodiafiltrazione con la tecnica HFR, può verificarsi con alcuni tipi di carbone attivato.

HFR is an integrated hemodiafiltration system that utilizes a double chamber filter to separate convection from diffusion. The ultrafiltrate is regenerated by passage through a sorbent cartridge made up of resin and activated carbon. A small percentage of patients using this technique had gastrointestinal symptoms that included nausea/vomiting, diarrhea and/or stomach cramps approximately 1-2 hours after the start of HFR. We undertook a series of investigations to try and elucidate the cause of these reactions. Since the majority of the patients were taking ACE inhibitors, attention was focused on contact phase activation. Healthy and uremic plasma were incubated with different components of the HFR circuit. The activated carbon caused a moderate activation of factor XII and production of kallikrein, while there was no activation for the lines, double filter or resin. Patients taking ACE inhibitors may be at risk for treatments involved with contact phase activation as ACE inhibitors also block the degradation of bradykinin. A new sorbent cartridge has now been developed that contains only resin.

[Clinical experience in HFR with a new resin-only sorbent cartridge]. / Sperimentazione clinica in HFR di una cartuccia rigenerante priva di carbone.

Adsorbent therapies have become increasingly popular over the last several years as they permit an additional method to selectively or non-selectively remove toxins. Adsorbents offer a unique removal strategy as they have an extremely high adsorption capacity due to their great surface area. This paper describes experiments that utilized a synthetic divinylbenzene styrenic resin cartridge to remove uremic toxins from chronic renal failure patients. The resin-only cartridge was tested as an alternative after a small number of patients (primarily taking ACE inhibitors) experienced gastrointestinal problems using hemodiafiltration with on-line regeneration (HFR). Subsequent laboratory evidence suggested that the particular carbon used in the cartridge was able to activate contact phase activation. This could potentially cause problems in patients taking ACE inhibitors, as they are unable to degrade bradykinin efficiently. The resin-only cartridge was tested in at 6 centers throughout Italy and included patients that had experienced previous reactions to the carbon-resin cartridge. At the conclusion of the study, no adverse reactions were reported and the cartridge exhibited excellent removal of b2 microglobulin and angiogenin.

[Optimization of a HFR sorbent cartridge for high molecular weight uremic toxins]. / Ottimizzazione di una cartuccia rigenerante per HFR nei confronti di soluti ad alto peso molecolare.

HFR is a hemodiafiltration method with regeneration of the ultrafiltrate. It consists of a double chamber filter that separates convection from diffusion. The ultrafiltrate exits from the convective filter, passes through a sorbent cartridge where uremic toxins bind to the sorbent. The "purified" ultrafiltrate is then returned to the patient. This study undertook a series of in vitro and ex vivo experiments to optimize the conditions for maximal adsorption and treatment efficacy. An emphasis was placed on a resin only cartridge as previous studies suggested that some patients may be sensitive to the activated carbon, particularly if they are taking ACE inhibitors.

[Long-term clinical experience in post-dilution HFR]. / Diciotto mesi di esperienza clinica su HFR on-line in post-diluizione.

PURPOSE: Hemodiafiltration reinfusion (HFR) is characterized by the use of regenerated ultrafiltrate as replacement fluid. We devised a new technique, post-dilution HFR, aimed at increasing the purification efficiency, treatment tolerability and at reducing inflammatory state. METHODS: We performed post-dilution HFR in six uremic patients during 18 months. Dialytic efficacy, filter blood rest and cytokine behavior were evaluated. RESULTS: Neither pyrogenic reactions nor other adverse phenomena were recorded. The tolerance to the treatment was excellent. We observed a high rate of urea extraction and optimal Kt/V values, a high extraction of beta2 microglobulin (beta2-m) and a reduction in blood rest; in addition, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) significantly decreased. CONCLUSIONS. The inversion of the standard HFR configuration allowed us to improve the removal of both urea and beta2-m, and the blood rest, with an optimal tolerability. Moreover, the reduction in cytokine levels could attenuate the uremic microinflammatory state.

[Comparison between two different on-line dialytic techniques: Standard HFR vs post-dilutional HFR]. / Emodiafiltrazione con reinfusione di ultrafiltrato rigenerato in pre- e post-diluizione: due tecniche on-line a confronto.

PURPOSE: Among hemodiafiltration (HFD) techniques, hemodiafiltration reinfusion (HFR) seems unable to achieve an optimal depurative efficacy. This study aimed to evaluate whether the HFR technique as suggested in its original configuration could be improved by devising a new technique (post-dilution HFR (PDHFR)) inverting the purification sequence to increase the purification efficiency of the entire system. METHODS: We performed standard HFR in six uremic patients during 6 months and, subsequently, during a further 6 months, PDHFR was performed. The dialytic efficacy of the two techniques and the filter blood rest were evaluated. In addition, we studied the behavior of cytokines during the inverted HFR sessions. RESULTS: We observed a significant increase in urea extraction and in Kt/V. An equally significant improvement was observed with regard to beta2-microglobulin (beta2-m) extraction and blood rest. Furthermore, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) significantly decreased after inverted HFR treatment. CONCLUSIONS: The inversion of the original configuration allowed us to improve the depurative efficacy of standard HFR, increasing the removal of both urea and beta2-m, and reducing the blood rest. Finally, it was notable that the reduction in cytokine levels could attenuate the uremic microinflammatory state.

[Bicarbonate balance in hemodiafiltration (HDF): a comparison between two infusion methods of on-line prepared solution]. / Bilancio dei bicarbonati in emodiafiltrazione (HDF): confronto fra due metodiche di reinfusione di liquido prodotto on-line.

PURPOSE: Hemodiafiltration (HDF) has high removal rates of low and middle-high molecular weight uremic toxins. We aimed to understand the efficacy and the safety in correcting on-line HDF acidosis. We compared two infusion methods of on-line prepared solution in HDF: HDF with an infusion solution produced from dialysate (HDF-OL) and HDF with a solution from patient ultrafiltrate after regeneration (HFR). METHODS: Eleven patients (four males, seven females) age 66 +/- 10 yrs, dialysis age 5.0 +/- 1.3 yrs, on anuria had two dialysis methods for the 1st session of the week, one HDF-OL and one HFR in 2 different weeks. In HDF-OL a high-flux polysulphone dialyser 1.8 m2 was used, in HFR a two-stage filter was used: polyetersulfone 0.7 m2 + SMC 1.95 m2 and a sorbent cartridge Selecta plus (Bellco) to regenerate the ultrafiltrate. HCO3- in the dialysis bath was 32 mmol/L. RESULTS: Plasma bicarbonates, before dialysis were 21.6 +/- 2.1 mmol/L on HDF-OL and 21.5 +/- 3.3 on HFR (p=ns), at the end they were 27.5 +/- 1.8 mmol/L on HDF-OL and 27.8 +/- 1.2 mmol/L on HFR (p=ns). On HDF-OL bicarbonates reached a plateau at mid session: 27 +/- 1.2, 27.5 +/- 1.2, 27.5 +/- 1.8 to 120, 180 and 240 min respectively. On HFR the plateau was reached more slowly: 26.1 +/- 1.9, 27.1 +/- 1.4, 27.8 +/- 1.2 with the same times. CONCLUSIONS: HFR-OL and HFR efficaciously corrected acidosis in a 4-h dialysis session. The same results, statistically and clinically, were achieved with infusion solution derived from dialysate and from solution from regenerated ultrafiltrate. In the latter, it was interesting that the global quality of the infusion solution was obtained from a close circuit from the patient ultrafiltrate.

[Steroids, interferon-alpha and ribavirin treatment of cryoglobulinemic glomerulonephritis concurrent with HCV infection]. / Terapia con steroidi, interferone-alpha e ribavirina in corso di glomerulonefrite crioglobulinemica HCV correlata.

The treatment of mixed cryoglobulinemia concurrent with HCV infection is still under debate. We report the case of a patient referred to our unit for a membranoproliferative glomerulonephritis associated with HCV infection. A nephrotic syndrome and a slight reduction of glomerular filtration rate were present. We treated him with alpha-interferon for six months and prednisone for two months. We achieved a remission of the nephrotic syndrome without any significant reduction of the viral load. One year after the therapy had been suspended, the nephrotic syndrome relapsed and subsequently responded to a combined treatment with interferon ribavirin and prednisone. HCV-RNA became suddenly and persistently negative.

Verapamil versus amlodipine in proteinuric non-diabetic nephropathies treated with trandolapril (VVANNTT study): design of a prospective randomized multicenter trial.

Angiotensin converting enzyme inhibitors (ACEI) are the most effective antiproteinuric agents and should be used as first-line drugs in both diabetic and non-diabetic proteinuric nephropathies. The role of calcium channel blockers (CCB) is much more controversial. In diabetic patients verapamil and diltiazem seem more effective than dihydropyridines in reducing urinary protein excretion, and have additive effects with ACEI, but little is available on chronic treatment of non-diabetic nephropathies for non-dihydropyridine CCBs. To test whether the combination of verapamil 180 mg or amlodipine 5 mg with trandolapril 2 mg reduces urinary protein excretion more than trandolapril 2 mg alone, we planned a prospective, randomized, double-blind, multicenter trial. The secondary aims are to evaluate the effects of both treatments on the selectivity of proteinuria and check their safety. Consecutive patients aged between 18 and 70 years with non-diabetic proteinuria > or =2 g/24 h and plasma creatinine < 3 mg/dl or creatinine clearance > or = 20 ml/min are asked to participate. After a four-week run-in during which previous antihypertensive therapy is withdrawn, a single dose of trandolapril 2 mg is given once a day in open conditions for four weeks. At the end of this period patients are randomly assigned to receive once a day, in a double blind fashion, either trandolapril 2 mg and verapamil 180 mg [plus a placebo], or trandolapril 2 mg plus amlodipine 5 mg. They are monitored after one, two, five and eight months.

Choosing new adsorbents for endogenous ultrapure infusion fluid: performances, safety and flow distribution.

Adsorption may notably contribute to the removal of uremic toxins and to the efficiency of hemodialysis. We examined different uncoated stationary matrixes, charcoals and synthetic resins to establish their adsorptive capacities in relation to low (urea, creatinine) and high molecular weight (beta2-microglobulin, myoglobin) compounds in in vitro conditions (steady state and flow-through) using isotonic solutions or uremic ultrafiltrate. Trace metal, particle release analyses and scanning electron microscopy of different adsorbents were performed. Dynamic flow-distribution studies were made using 99Technetium and analysing the different regions of interest by single head gamma-camera. We show that adsorbents may differ greatly as to their adsorptive capacity depending on flow rate, nature, and total mass of the compounds to be removed from the ultrafiltrate. These studies suggest a methodological approach for screening stationary matrixes for possible application in hemodialysis.

Adsorption in hemodialysis.

The use of sorbents in different blood purification techniques is reviewed. The sorbents used in these therapies are divided into two groups: (1) Adsorption occurs fundamentally because of the hydrophobic properties of the sorbents. In this group, the sorbents used in different dialysis techniques are charcoal and nonionic macroporous resins. (2) Adsorption occurs by chemical affinity, such as ion exchange resins and chemisorbents. Sorbents were initially used in hemoperfusion, which caused many adverse events; later, with the use of coated charcoal, these undesired effects decreased or disappeared, but the adsorptive properties, water control, and acid-base balance still created problems. For these reasons, the use of sorbents in the treatment of chronic renal failure was almost totally discontinued. Little by little, interest in these substances has reappeared, and at present, they have been used in combination with other blood purification techniques such as hemodialysis, hemofiltration, peritoneal dialysis, and finally, hemodiafiltration. Within the various hemodiafiltration techniques, paired filtration dialysis-charcoal is being used to regenerate the ultrafiltrate, which is used as the replacement fluid. Charcoal regenerates the ultrafiltrate and transforms it into a physiological solution with a normal electrolyte composition, calcium, bicarbonate, and glucose, having eliminated the majority of both middle and large molecule uremic toxins. If regeneration is done properly, this replacement fluid is bacteria and endotoxin free. Studies currently are underway on the adsorption of different inflammatory substances in the ultrafiltrate, which could lead to improvement in the biocompatibility of the system.

Hemodiafiltration with online regeneration of the ultrafiltrate.

The concept of regeneration of dialysis fluids and of ultrafiltrate in particular has been recently revisited. Hemodiafiltration with online regeneration of the ultrafiltrate allows the concomitant infusion of sodium, calcium, and bicarbonate. Here, we studied the adsorptive characteristics of an integrated two-step sorbent system relative to different solutes present in the ultrafiltrate: sodium, calcium, phosphate, bicarbonate, uric acid, creatinine, and beta2-microglobulin. In vitro studies were performed in order to differentiate the relative roles for each sorbent (mineral-activated charcoal or hydrophobic resin) in adsorbing a given solute. Ex vivo studies were performed in order to evaluate the presence of cytokines (interleukin-1 beta and tumor necrosis factor-alpha), of cytokine (interleukin-1 beta and tumor necrosis factor-alpha)-inducing activities, and of the cytokine release in response to exogenous bacterial lipopolysaccharide by normal whole blood incubated with ultrafiltrate samples obtained at 15, 120, and 240 minutes after the start of treatment. The results of the present studies show the presence of immunomodulatory substances in the ultrafiltrate and the significant (P < 0.01) increase in the lipopolysaccharide-induced release of both interleukin-1 beta and tumor necrosis factor-alpha. The biological relevance of the ultrafiltrate and the possible relevance of the online, endogenous reinfusion are discussed.