The influence of dialysis treatment modality on the decline of remaining renal function.

A retrospective investigation was undertaken in which the rate of decline of residual renal function (RRF), estimated from creatinine clearance, was compared in 55 continuous ambulatory peritoneal dialysis (CAPD) and 57 hemodialysis (HD) patients for whom a minimum of four (mean of 7.6) well-spaced historic measurements of residual clearance were available. Because of the intrinsic variability that attends such data, specialized nonlinear, growth curve statistical methods were employed. Residual function was found to decline exponentially after the onset of therapy in both cohorts. The rate of decline in the HD group was twice that of the CAPD group (5.8% +/- 0.4% per month for HD vs 2.9% +/- 0.3% per month for CAPD; difference significant at p less than 0.0001). This difference remained highly significant (p less than 0.01) when corrected for other potential risk factors such as age, gender, hypertensive status, and use of angiotensin converting enzyme inhibitors in patients with diabetic or other forms of glomerular nephropathy. Differences between cohorts were not significant for patients with other diagnoses (p greater than 0.1) although the size of some of these subsets was very small. The physiologic mechanism for the more rapid fall-off of RRF on HD remains speculative, but could be related to renal ischemia secondary to intratreatment hypovolemia and/or to nephrotoxic effects of the inflammatory mediators of extracorporeal circulation.

Plasma water filtration and lymphatic uptake during peritoneal dialysis.

To clarify further the extent, pathways, and significance of convective transport during peritoneal dialysis, acute transport studies were conducted in which five continuous ambulatory peritoneal dialysis (CAPD) patients underwent 6 hr dialyses (2 L infusate with 2.25% dextrose) on 2 successive days, with multiple sampling of both blood and peritoneal dialysate. Concentrations of permeants (urea, creatinine, uric acid, beta 2 microglobulin, and apolipoprotein A) and a radiolabeled marker (125I-polyvinyl pyrollidone [PVP]) were determined at 20-30 min intervals in dialysate and every 90 min in plasma. Intraperitoneal volumes and lymphatic flows were calculated from rates of dilution and disappearance of 125I-PVP. Intratreatment lymphatic flow rate averaged 76 +/- 15 ml/hr. Although lower than observed in small animal models and reported by some clinical groups, this level of lymphatic drainage was still sufficient to decrease net patient weight loss by approximately 50% and to resorb approximately 15% of metabolites in the peritoneal cavity, independent of molecular weight. Transcapillary ultrafiltration ranged from 7.4 +/- 1.5 ml/min at 10 min into the exchange to 1.3 +/- 1.5 ml/min at 345 min. Reverse ultrafiltration, from the peritoneal cavity back through capillary vasculature to the patient, was not observed in any patient in this study.

Vaccination for prevention of CAPD associated staphylococcal infection: results of a prospective multicentre clinical trial.

124 stable CAPD patients from 8 Australian and 3 New Zealand centers were randomly assigned in a blinded fashion to one of two groups to study the effect of vaccination using commercial preparations consisting of a combined staphylococcus toxoid and whole killed staphylococci (SB) or normal saline solution (SS) on the incidence of peritonitis and exit site infection and S. aureus nasal carriage over a 12-month prospective period. In addition, levels of IgG, IgA, IgM, C3 and C4 were monitored during the trial period in serum and dialysate; serum levels of anti-alpha hemolysin and dialysate levels of fibronectin and specific antistaphylococcal antibodies were also measured. Over the period, treatment with SB or SS did not affect the incidence of peritonitis, catheter-related infection or S. aureus nasal carriage. However, vaccination with SB elicited a significant increase in the level of serum anti-alpha hemolysin throughout the 12 month duration of the study, although the level of increase was unrelated to the subsequent rate of peritonitis. Vaccination with SB but not SS elicited a significant increase in the dialysate level of specific antibodies against S. aureus. Serum levels of IgG, IgA, IgM, complement C3 and C4 were within the normal range in the CAPD patients studied and remained unaffected by vaccination with SB. In addition, dialysate levels of IgG, IgA, IgM, complement C3 and C4 were 50-100 times lower than corresponding serum levels and remained unaffected by vaccination. In summary, immunisation with an anti-staphylococcal agent was not successful in reducing peritonitis or exit site infection in CAPD patients.

Long-term continuous ambulatory peritoneal dialysis. Mass transfer and nutritional and metabolic stability.

Long-term mass transfer and nutritional and metabolic stability of end-stage renal disease patients maintained on continuous ambulatory peritoneal dialysis (CAPD) continue to be of concern. This study longitudinally monitored 43 Japanese CAPD patients (29 males, 14 females) from three centres within the Tokyo Metropolitan Area for an average period of 15 +/- (SD) 8 months. The mean time for patients on CAPD at study initiation was 18 +/- 15 months. Monitored parameters included urea and creatinine mass transfer coefficients, clearances and blood levels, ultrafiltration, lipid levels, dietary protein intake, and weight. Lipid data were also gathered retrospectively from patient records from the time of CAPD initiation. The results were analyzed using regression growth curve analysis and analysis of variance. Statistically significant linear rises with time were apparent only for the creatinine mass transfer coefficients, although this was not considered clinically significant in terms of changes either in peritoneal creatinine clearances or ultrafiltration. Serum cholesterol levels were found to rise significantly above pre-dialysis levels 11 months after CAPD onset, thereafter returning to levels not significantly above baseline levels. In summary, CAPD provided stable, acceptable treatment over the study period.

Is the peritoneal membrane durable indefinitely?

In general, the permeability characteristics of the peritoneal membrane are well maintained with time in the context of current technique survival rates. Some data would suggest that there is a tendency toward hyperpermeability in long-term PD patients; in a much smaller group of patients this may manifest itself as a loss in ultrafiltration capacity in the short term, that is within 2-4 years after CAPD initiation. A reduction in factors, which continue to have a significant negative effect upon technique survival, such as peritonitis and catheter-related infection will see patients remaining on the therapy for longer. This may place a sharper focus on ultrafiltration loss in the PD population, particularly that associated with increases in the permeability of the peritoneum. However, until such time as significant improvements occur it is likely the peritoneal membrane will continue to be more durable than the therapy in the vast majority of patients. It is now becoming clearer that the rate of decline of residual renal function (RRF) may be an important factor in the development of sequelae associated with inadequate dialysis. The role of RRF has often been overlooked when the clinical manifestations of inadequate UF and solute removal have become apparent and further study is required to determine the contribution of residual diuresis to the table of prognostic factors associated with long-term stability of the PD patient. Nevertheless, it is clearly an important parameter worthy of considerable future focus. Although membrane performance appears well maintained in general, routine monitoring of the mass transfer performance of the peritoneum should be performed. Assessment will facilitate focussed dialytic management and allow the clinician to recognise and pre-empt potential problems resulting from inadequate dialysis associated with decreasing or increasing membrane permeability in the small number of patients so affected: such monitoring should include measurement of the mass transfer coefficient at onset and every 6-12 months thereafter. However, the monitoring of RRF and overall solute clearance is perhaps of more significance in view of the contribution of RRF to overall dialytic prescription. The routine assessment of these parameters is also encouraged.

The role of lymphatic drainage in peritoneal mass transfer.

Peritoneal lymphatic drainage has recently been shown to be a contributing factor to both clearance and fluid removal patterns during continuous ambulatory peritoneal dialysis. In this report peritoneal transport equations are derived and compared and contrasted with existing models that ignore this term. It was found that for solutes for which the sieving coefficient may be assumed to equal unity, such as urea and creatinine, the values of the mass transfer area coefficient (KoA) are overestimated by the value of the lymphatic drainage rate. In this instance, corrected KoA may be obtained simply by subtracting lymphatic flow rate from the KoA calculated by traditional methods. For larger solutes, such as beta 2-microglobulin, for which the sieving coefficient may be assumed to equal zero, the value of mass transfer coefficient was underestimated to varying degrees; however, for values of lymphatic drainage rate less than 60 ml/h the effect will not be clinically measurable. A theoretical model is used to plot the dependence of net fluid removal on peritoneal lymphatic flow, glucose KoA, and hydraulic permeability. Reduction in net ultrafiltered volume, and hence estimation of transperitoneal ultrafiltration, is directly proportional to accumulated lymphatic drainage.

Beta-2 microglobulin removal during continuous ambulatory peritoneal dialysis (CAPD).

Beta-2 microglobulin (B2M) handling in continuous ambulatory peritoneal dialysis (CAPD) was characterized in acute and chronic clinical studies. Average clearance rate was 0.7 mL/min and mean mass transfer coefficient, KoA, was calculated to be 0.95 cm2/min; these values are in the range expected from extrapolation of published data for other large solutes. In chronic studies with both anuric and oliguric populations, CAPD was shown to be much more effective than conventional hemodialysis in removing B2M and, in fact, CAPD removal rates were equivalent to those reported for high flux dialysis therapies. However, this greater extraction was not associated with any clinically significant reduction in circulating plasma concentrations. These trends remained valid in both the anuric and oliguric subsets of the study population.

Loss of ultrafiltration in continuous ambulatory peritoneal dialysis (CAPD).

Fifteen patients on long-term continuous ambulatory peritoneal dialysis (CAPD) were assessed with respect to net ultrafiltration capacity. Eight patients were defined as having good and seven as having poor ultrafiltration on the basis of net ultrafiltrate obtained/mmol glucose infused. Subsequently, dialysate was sampled at times 0, 1, 15, 30, 60, 90, 120, 180, and 240 min. No difference in residual volume was observed between the groups. A significantly greater decrease in dialysate sodium during the initial dialysis period in those patients with good as compared to those with poor ultrafiltration occurred, reflecting a greater transcapillary movement of electrolyte poor ultrafiltrate. In those with good ultrafiltration, glucose transfer was normal in five and rapid in three, suggesting the latter had low rates of lymphatic reabsorption. Five of seven patients with poor ultrafiltration had no fall in dialysate sodium in association with a high rate of glucose transfer, suggesting a low rate of transcapillary water movement and normal to high lymphatic absorption. Two patients with low ultrafiltration had an initial fall in dialysate sodium with a normal glucose transfer and thus net ultrafiltration is low due to elevated lymphatic reabsorption. We thus propose that the relative contribution of transcapillary water movement and lymphatic reabsorption can be determined by assessing net ultrafiltration and dialysate sodium concentration in conjunction with solute transfer.

Mixed-mode therapy: kinetic analysis and acute clinical evaluation.

A mixed therapeutic modality was devised in which patients with chronic renal failure were treated with a combination of continuous ambulatory peritoneal dialysis (CAPD; two daily 4-hour exchanges per day; 16 h dry belly) and hemodialysis (1 session per week). Kinetic modeling analysis indicated that a time-averaged urea concentration equivalent to CAPD could be obtained with a Kt/V value of 1.2-1.6, depending on patient parameters, for the single-weekly hemodialysis. The therapy format was acutely evaluated in a 2-week clinical trial on 4 patients. Excursions in small-solute concentration were virtually equivalent to those predicted from theory. Adequate fluid removal was obtained in the 2 CAPD exchanges and blood pressure was well controlled. As a result of the success of the acute trials, and since this format may offer potential lifestyle advantages to patients who possess dual access, a chronic trial of mixed-mode therapy seems advised.

Evolution of transport theory in CAPD.

Current mathematical approaches describing solute and mass transfer during CAPD are based on a compartmental model, assuming the body and the peritoneal cavity to be different compartments and the peritoneal membrane to be a more or less complicated interface. Whereas simplified mathematical approaches may prove useful for routine clinical determination of mass transfer characteristics, more complex models may better serve developmental and theoretical purposes.

A model of ultrafiltration and glucose mass transfer kinetics in peritoneal dialysis.

We have investigated the variation with dwell time of dialysate volume and glucose concentration during continuous ambulatory peritoneal dialysis using a one-pool model. No assumption was made regarding the ultrafiltration rate that was calculated by the model. Results show that the volume ultrafiltered during dwell time is an increasing function of peritoneal membrane hydraulic permeability and a decreasing function of glucose mass transfer coefficient (MTC). For large MTC and low initial glucose concentration there is reabsorption of dialysate into the blood at large dwell times. For a 6 h dwell time, glycerol (92 daltons) is a more effective osmotic agent than glucose (198 daltons) at the same weight concentration. These results are in quantitative agreement with published clinical studies.

Adequacy of dialysis: marker molecules and kinetic modeling.

The effective use of kinetic modeling to assess adequacy of dialysis, based upon marker molecules, is in its infancy. However, for the patient, perhaps the most identifiable benefit of modeling is that the technical parameters of the therapy are at least being measured and monitored. With regard to choice of marker molecules, the National Dialysis Cooperative Study (NCDS) group, in choosing urea as the reference molecule, has given a useful impetus to its wider use. Since urea is directly connected with dietary protein intake and its net generation is also directly correlated with that of other metabolites, its application as a marker molecule makes good sense. Analysis of the NCDS data has permitted identification of a very useful quantitative parameter of minimal dialysis therapy based on urea clearance and distribution volume and dialysis time. For thrice-weekly dialysis, normalized whole body urea clearance (Kt/V) should be greater than or equal to 1.0 and less than approximately 1.5. Although this alone does not guarantee adequate dialysis, it does alert the dialysis staff to the potential for both under- and over-dialysis. It would thus appear that currently the most reliable and useful means by which to apply modeling techniques to dialysis therapy is urea kinetics. In time, the application of more broad-based modeling techniques to dialysis therapy will provide more clearly identifiable clinical benefits, as well as the already realizable economic benefits.

Laboratory diagnosis of peritonitis in patients treated with continuous ambulatory peritoneal dialysis.

Patients treated with continuous ambulatory peritoneal dialysis (CAPD) are constantly exposed to microbial invasion of the peritoneal cavity and rapid microbiological diagnosis of peritonitis is essential. Aseptic peritonitis is diagnosed in a high proportion of episodes when small volumes of dialysate are cultured. The aims of this study were to enumerate the microorganisms associated with clinical peritonitis and compare the efficacy of various culture systems for laboratory diagnosis of peritonitis. Four qualitative culture systems were compared: low (1 ml) volume and high (10 ml) volume inoculations of broth media, centrifugation (10 ml) followed by culture of the sediment and filtration (less than or equal to 100 ml) followed by culture of the filter. The pour plate and drop plate were the 2 quantitative methods used. Results of this study indicate that culture of 10 ml fluid volumes is comparable to culture of larger volumes sampled by filtration. Low volume cultures of fluid resulted in a lower proportion of positive cultures. The low numbers of viable microorganisms often found in dialysate from patients with peritonitis supports the concept of culturing a minimum of 10 ml of fluid.

Analysis of immunoglobulin G kinetics in the non-steady state.

The effect of specific intravascular IgG depletion on IgG catabolism, generation, and intrabody transfer has been studied in rabbits. In contrast to previous studies, the radiolabeled IgG kinetics were analyzed in the non-steady state. A two-pool model was used to determine IgG distribution, catabolism, generation, and intrabody mass transfer after intravenous injection of 125I-IgG. Circulating IgG was then specifically removed by plasma perfusion through a Protein-A Sepharose column in an extracorporeal circuit. Based on the two-pool analysis, IgG catabolic clearance fell after IgG removal (1.0 ml/hr vs. 0.7 ml/hr), and mean generation rate was unchanged. Plasma levels rose 20 hours after IgG removal as a result equally of contributions from intrabody transfer and of generation. Model parameters from plasma 125I decay analysis overestimated plasma 125I levels in the first 24 hours after removal, although predicted endogenous levels corresponded well with experimental results over a 7-day period. Rapid intravenous infusion of a 7% body weight volume of saline solution during IgG removal resulted in 50% greater plasma levels of 125I-IgG 24 hours after removal. This indicated that an increased lymphatic flow had occurred, resulting in increased IgG transfer from the extravascular to the intravascular space. The two-pool model adequately describes circulating IgG levels after specific IgG removal. Catabolic clearance was found to be a function of IgG level, whereas generation does not appear to be similarly dependent. Both the two-pool model and saline infusion procedure may be applied directly to the planning and optimization of plasma exchange therapy regimens in human autoimmune disease.