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Several strategies have been proposed to increase dialysis efficiency in order to reduce dialysis treatment time. Paired filtration dialysis (two-chamber technique) is a new technique combining the advantages of highly permeable membranes and convective transport with the high depurative efficacy of diffusion. The system operates with two units in series (hemofilter + dialyzer) with membranes of polysulfone and hemophan, respectively. A detailed analysis of the hydraulic properties of the system and its possible optimization in terms of depurative efficiency is reported in this paper. In vitro and in vivo tests provided data sufficient to draw some hypotheses on a new utilization of the system. The system appears to be adequate for operating under conditions of high blood flows, however, some limitations were evidenced during our evaluation: the convective component may be insufficient and further increases are impossible because of the limiting effect of the low surface area of the hemofilter; the configuration in which the weight loss is achieved in the hemofilter exposes to the risk of backfiltration in the dialyzer, reducing the benefits of a highly biocompatible system, and the use of acetate in the dialysate and/or lactate in the substitution fluid may interfere with a satisfactory correction of metabolic acidosis. On the basis of our evaluations, some changes can be proposed such as: (1) increased surface area of the hemofilter; (2) use of blood flows higher than 300 ml/min; (3) use of bicarbonate in the dialysate and in the replacement solution; (4) increased convective component with ultrafiltration rates of 50-60 ml/min and full replacement with substitution fluid in between the two filters, and (5) weight loss achieved in the dialyzer with a constantly positive transmembrane pressure. With such a modification of the operative conditions, paired filtration dialysis can be probably applied as a highly efficient dialysis technique in a large number of patients with a significant reduction of dialysis treatment time.

Pathophysiology of peritoneal ultrafiltration is analyzed in the present study. Peritoneal equilibration test is the easiest procedure to study in detail the possible causes of failure to control the ultrafiltration rate in patients undergoing peritoneal dialysis. Membrane failure, reduction in peritoneal blood flow, excessive lymphatic reabsorption catheter malposition, and fluid sequestration are the most common causes of ultrafiltration loss. Pharmacologic manipulation of peritoneal membrane, correction of mechanical inconvenients, reduction in peritonitis rate and in the level of immunostimulation of the mesothelial macrophages, together with a careful policy in terms of glucose concentration in the dialysate and dwell times may contribute not only to treat different forms of ultrafiltration loss but also to prevent their incidence.

Alpha 1-Antichymotrypsin (alpha 1-AK) and alpha-1-antitrypsin (alpha 1-AT) represent a defense mechanism to protect the tissues from proteolytic enzyme activity. We studied the implication of alpha 1-AK and alpha 1-AT in glomeruli of patients with different nephropathies based on the analysis of 52 paraffin-embedded renal biopsies with alpha 1-AK and alpha 1-AT antisera. The results demonstrate an intense alpha 1-AK glomerular staining in renal biopsies from patients with minimal-change disease, while a minor staining of this protein was found in the other nephropathies. No significant evidence of alpha 1-AT deposits was observed in our cases. Our findings suggest that when alpha 1-AK is lacking in glomeruli the defense mechanisms against proteolytic enzymes may not be efficient enough to protect the glomerular structures and limit the damage. Since alpha 1-AK is a reactant of the acute phase of inflammation, it may be considered as a marker of activity for monocyte-macrophages in glomerular damage.

The goal of shortening dialysis treatment time has stimulated the development of new, highly efficient dialytic strategies. In this study the Authors compared four different short dialysis treatments in terms of efficiency, clinical tolerance, technological investment and costs: 1) Rapid bicarbonate dialysis with 1.5 sq.m. cuprophane membrane; 2) High flux biofiltration with 1.2 sq.m. AN69S hollow fiber membrane; 3) Hemodiafiltration with 1.2-1.9. sq.m. polysulphonic hollow fiber hemodiafilters, and 4) High flux hemodiafiltration with two serial hemodiafilters with AN69s membrane (total 2.4 sq.m.). Hydraulic properties and solute clearances at different blood flows (300-500 ml/min) were tested for each technique. Once the optimal operative level was established three patients were treated with each technique for at least six months. Since BUN clearance averaged 310 ml/min, the treatment duration varied from 120 to 180 min/session with KT/V always higher than 1. The average protein catabolic rate was 0.9 g/kg/24h. Clinical tolerance was generally good, slightly better in treatments with a high convective component. Despite the greater efficiency of treatment No. 4, the technological requirements and costs are such that the others are currently more feasible and acceptable in clinical routine. The study demonstrates that reduction of dialysis treatment time is possible in all centres in a selected population with adequate blood access. Treatment No. 1 can even be performed with standard equipment and cuprophan membranes, while bicarbonate in the dialysate is mandatory. The real limit to shortening treatment time seems to be related to the maximal rate of ultrafiltration achievable in the patient during dialysis.

To increase the efficiency of continuous arteriovenous hemofiltration (CAVH) in cases of severe catabolism, we used a modified CAVH treatment, called arteriovenous hemodiafiltration (AVHDF), in 4 patients. The transport of solutes was increased by providing the infusion of a counter current flow of urea-free solutions in the UF compartment of a standard CAVH circuit. Patients were treated with standard CAVH and, when a more efficient treatment was required, intermittent daily sessions of AVHDF were performed using the same filter and lines. The urea kinetic study enabled the calculation of the time needed to perform AVHDF, in addition to standard CAVH, to maintain the blood urea nitrogen (BUN) level under control. A dialysate flow rate of 300 ml/min made it possible to increase the urea nitrogen mass transfer rate from 10 to 65 mg/min and the clearance from 10.5 to 37.5 ml/min. The addition of AVHDF to CAVH enabled the control of BUN levels in the 4 patients affected by acute renal failure and a severe catabolic state. The technique is simple, does not require additional devices, and maintains the advantages of CAVH providing a better efficiency in terms of solute removal.

In 21 uraemic subjects not yet requiring dialysis, the serum values of citrate, fumarate, oxalacetate and malate were significantly increased, so that the sum of the concentrations of the TCA-cycle intermediates were increased threefold compared to that of 18 control subjects. The replenishment of TCA intermediates could, in theory, occur by several anaplerotic reactions, mainly those catalysed by pyruvate-carboxylase and malic enzyme. The overall pattern detected in uraemic patients is similar to that observed in rat skeletal muscle during exercise, in which increased acetyl CoA has been found.

The amount of fluid withdrawn by ultrafiltration in a dialysis session plays an important role in regulating the acid-base status of patients. It has been previously demonstrated that an interdialytic weight gain of 3 kilograms requires the removal of 3 liters, mostly of extracellular fluid, which may contain 60-70 mMols of bicarbonate. Such losses require an increase in the buffer mass transfer to achieve a good buffer balance. The importance of interdialytic weight gain (IWG) on acid-base status was evaluated in two significantly different periods. In the period where the IWG was lower, predialytic pH and HCO3 were significantly higher than in the alternate period. Since dialysis schedule, dialysate buffer, daily protein intake and given medications did not differ during the two periods, we conclude that a reduced ultrafiltration due to less weight gain betters predialytic acid-base status.

In vitro and in vivo studies were performed on 10 dialyzers with 5 microns thick cuprophan membrane to evaluate hydraulic properties and permeability to solutes. Inlet and outlet pressures of the filter were measured at different blood flows to assess the resistance of the device and the end-to-end pressure drop. Hysolated ultrafiltration was performed to evaluate the spontaneous filtration at increasing blood flows, the ultrafiltration rate at different transmembrane pressures and, finally, the sieving coefficients for solutes. Standard hemodialysis was also performed to study the clearances throughout a 4-h session. During hysolated ultrafiltration the UF rate was increased up to 37 ml/min showing a very high hydraulic permeability of the membrane. The spontaneous filtration rates related to blood flow were quite low. Since the end-to-end pressure drop in the filter was also relatively low at high blood flow we may conclude that the geometry of the device is able to dissociate the influence of blood flow on the hydrostatic pressure inside the filter. This results in a easy modulation of the membrane permeability to water. Sievings were surprisingly high and clearances were stable along the dialysis session (BUN = 196 ml/min, creatinine = 161 ml/min and phosphate = 163 ml/min).

A condition of metabolic alkalosis has been generally observed in patients undergoing regular biofiltration (BF). The aim of this study was to assess buffer kinetics during a dialysis session in five patients regularly treated by BF for 10 months (dialyzer Biospal 3000S, Qb 301; Qd 545; UF 36.76 ml/min; dialysate CH3 COO 38 mEq/L; replacement fluid 1000 ml/h with HCO3 100 mEq/L solution). As usually happens using dialyzers with high surface area and permeability, large HCO3 losses (756 +/- 112 mEq) and CH3COO uptakes (677 +/- 152 mEq) were observed. Acetate plasma levels rose to 10.4 mEq/L, a value potentially dangerous to the cardiovascular system. The dialytic buffer gain (acetate uptake + HCO3 administered - HCO3 loss) was high (230 +/- 137 mEq/dialysis) and excessive for patients' needs. It is therefore very important to reduce either the acetate concentration in dialysate or the amount of reinfused bicarbonate. In view of the plasma acetate levels it is preferable to use a dialysis solution containing less acetate.

We carried out an in-vivo and in-vitro evaluation of a new polyamide hollow fiber hemofilter especially designed to operate under conditions of low pressure and low blood flow, such as in continuous arteriovenous hemofiltration (CAVH). The results obtained suggest that this filter is a prototype of a new generation of hemofilters especially designed for CAVH. Its low resistance permits its use even in patients with severe hypotension. The high blood flows achieved at a given pressure reduce the risk of clotting and increase the ultrafiltration rate. When an average ultrafiltration of 20-25 ml/min is achieved in 24 hours CAVH becomes very efficient, and alternative techniques to increase its efficiency are no longer required.

The transport mechanisms governing solvent and solute removal during CAVH were elucidated on the basis of in vitro and in vivo observations. Using a typical hemofilter (Diafilter D-20, AMICON), filtration rate rose with inlet blood flow rate until an asymptote was reached at blood flows of approximately 150 ml/min. The onset of the asymptote coincided with transition from a regime controlled by oncotic pressure (filtration pressure equilibrium), to one governed by simple Darcy's law filtration behaviour. Subsequent measurements showed that under clinical conditions, CAVH is generally in the pre-asymptotic regime and operates at filtration pressure equilibrium. These observations offer the theoretical bases for a new design for CAVH hemofilters. As a possible corollary, middle-molecule sieving coefficients were found to be stable with time during CAVH in vivo, whereas in chronic mechanical hemofiltration they declined significantly during clinical treatment. The sieving coefficients, however, were lower in mechanical hemofiltration from the beginning of the session. These observations suggest that the measured sieving coefficient for a membrane is not necessarily a constant directly and solely related to the membrane standard reflection coefficient for a given solute. Concentration polarization and the ultrafiltration rate per unit of surface area may in fact have a major effect on the final concentration of solutes in the ultrafiltrate.

The feasibility and reliability of a short dialysis technique performed with standard dialysis equipment and a modified cuprammonium rayon hollow-fibre filter has been studied. The hydraulic response of the filter and membrane to high blood flows and transmembrane pressures were tested in vitro and the maximal clearances of different solutes achievable during high-flux bicarbonate dialysis were studied in vivo. Clinical studies were undertaken to evaluate the long-term effects of the short, highly efficient dialysis therapy. Six patients were treated for more than a year with single-pass bicarbonate dialysis with a blood flow of 500 ml/min, dialysate flow of 700 ml/min, and average duration of 150 min/session three times weekly. The treatment showed an adequate efficiency with an average KT/V greater than 1. All patients obtained an average blood urea nitrogen during the study of less than 80 mg/dl and an average protein catabolic rate of 0.9 g/kg per 24 h. The treatment was well tolerated by all patients and, on echocardiography, no significant changes in myocardial function were detected after one year of therapy. The treatment is efficient, well tolerated, simple to monitor and does not require the use of synthetic membranes or machines with advanced technology. Thus the reduction of dialysis treatment time is feasible in all centres at a relatively low cost.

A new system for ultrafiltration control during hemodialysis is described. The apparatus consists of a computer operated system of load cells that register variations in weight of the outlet dialysate versus inlet dialysate. Once the weight loss of the patient has been established, the gravimetric control operates on the dialysate circuit to obtain the transmembrane pressure adequate to achieve the desired ultrafiltration rate and patient weight loss. The system can be used as a complete dialysis machine or as a separate module that can be adapted to any standard dialysis machine. This module was tested in more than 220 dialysis sessions, using different membranes and ultrafiltration rates. The difference between the scheduled and the real weight loss was always less than 100 g at the end of the dialysis session. The number of technical interventions required were few, as was the rate of complications related to the system. The system is safe and reliable and offers a low cost opportunity to improve dialysis tolerance by accurate and progressive ultrafiltration during the session.

Bicarbonate has been proposed as buffer in CAPD solutions in recent years instead of lactate and acetate. The present study is designed to evaluate peritoneal bicarbonate kinetics using bicarbonate solutions. Seventy kinetic studies have been performed in 7 patients treated with 2 CAPD solutions containing 35 mmol/l (A) and 27 mmol/l (B) of bicarbonate. The changes in dialysate bicarbonate concentration at different dwell times were correlated with bicarbonate blood levels. Furthermore after 2 hours of dwell time and at subsequent observations, no differences in dialysate bicarbonate concentration were found between A and B solutions at the same bicarbonatemia. Thus a feedback between bicarbonate absorption and bicarbonate blood concentration was observed. If the amount of bicarbonate transferred to the patient is over the metabolic acid production, bicarbonatemia will rise: consequently bicarbonate dialysate absorption will decrease. After a few days, an equilibrium point will be reached. In this condition the bicarbonate absorption is equal to metabolic acid production and, in stable clinical conditions, a stable acid base status will be maintained by the patient. Our studies empirically demonstrated that the equilibrium is reached when a difference of 5 mmols between blood and inlet dialysate bicarbonate concentration is observed. Consequently to achieve 25 mmol/l of bicarbonatemia, the bicarbonate concentration of CAPD solution should be about 30 mmol/l.

The treatment of acute renal failure (ARF) in the newborn with hemo- or peritoneal dialysis is technically difficult and may even be contraindicated. As in the adult, continuous arterio-venous hemofiltration (CAVH) may be an alternative therapy. We used CAVH in the treatment of four newborns with ARF of different etiology. Two brachial, one femoral and one umbilical arteries were cannulated as arterial access, while three jugular and one umbilical veins were used as venous return. An Amicon 0.005 m2 Polysulphon Hollow Fiber hemofilter was connected to the patient with shortened pediatric hemodialysis lines. Total blood volume of the extracorporeal circuit was 15 to 22 ml. Before starting the procedure, an initial bolus of heparin was administered to the patient (100 i.u./kg body wt) and a successive continuous heparin administration was provided during the treatment at the rate of 5 to 7 i.u./kg/hr. Hyperalimentation and/or buffer solutions were used as replacement fluids and were administered according to the patient's fluid balance. mean data in the four patients are summarized as follows. The age of the patients ranged from two to 12 days, while the average body weight was about 3 kg. The ultrafiltration rate during the treatment averaged 0.9 ml/min with a plasma flow ranging from 9.8 to 19.6 ml/min. The treatment duration varied from 30 to 86 hrs. The treatment was well tolerated (patients 1 and 2 recovered, and patients 3 and 4 died due to complications unrelated to the treatment). Arterial pressure remained stable during the procedure. Metabolic acidosis, when present, was corrected by increasing the amount of buffer administered. BUN was maintained below 60 mg/dl in three patients.(ABSTRACT TRUNCATED AT 250 WORDS)