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Clearances of small and large solutes were measured at increasing transmembrane pressure in 3 types of parallel plate dialyzers. Both laboratory and clinical studies were performed. As in previously reported studies in coils, diffusive transport appears to decrease as transmembrane pressure increases. This may reflect blood channel widening, bath channeling, and/or membrane masking by mesh support. For small solutes, decreases in diffusive transport were enough to offset gains by solvent drag and total clearances decreased. In some studies, decreases in small solute clearances with increasing ultrafiltration were large enough to compromise dialysis efficiency.

The use of sorbents in dialysate to increase solute clearances in continuous ambulatory peritoneal dialysis (CAPD) was investigated. With in vitro simulations of CAPD, the kinetics of irreversible binding of creatinine to activated charcoal were assessed. Cellulose dialyzer fibers were submerged in two liters of dialysate for 3-8 hour exchanges. Perfusate was pumped single pass through the fibers. Commercial dialysates with 1.5% and 4.25% dextrose as an osmotic agent were controls. Experimental exchanges contained either large or small particles of activated charcoal. Unencapsulated and collodion encapsulated large particles were also studied. From the perfusate side, creatinine, clearance and mass transfer were determined; dialysate/perfusate ratios (D/P) of free creatinine concentrations were assessed. We found that incorporation of small unencapsulated particles of activated charcoal would double both clearance and mass transfer of creatinine. It also maintained D/P values less than 0.6 even up to 8 hours. Small particles absorbed more than 10 times more creatinine per gram than large particles. Significant differences between encapsulated and unencapsulated large particles were not found. In summary, activated charcoal might double creatinine removal per exchange in CAPD. Animal studies of collodion encapsulated small particles and other sorbent-enzyme systems in CAPD dialysate solutions seem warranted.

Hollow fiber dialyzers are currently available with either regenerated cellulose or thinner walled cuprophan fibers. In vitro and clinical studies were undertaken to compare a cellulose with a cuprophan dialyzer in regard to (1) UF's, (2) small and large solute clearances at high and low TMP's, (3) SC's, and (4) effects of ultrafiltration on diffusive and convective components of clearances. The results show that per square meter of surface area, the cuprophan dialyzer has higher rates of UF per TMP and greater clearances, particularly of larger solutes; also with cuprophan the SC for vitamin B12 is higher. Thus all findings suggest greater permeability of cuprophan fibers. In both dialyzers, total clearances increased with UF by amounts compatible with predicted increases in convective transport; diffusive transport remained stable as TMP was increased.

Peritoneal solute equilibration studies during prolonged intraperitoneal dwell were performed in patients with psoriasis and normal renal function, and compared to patients with renal failure undergoing peritoneal dialysis. Calcium, phosphorous, uric acid and protein equilibration were faster in uremics. No differences were observed for sodium and chloride. Mass transfer area coefficients (a measure of the mass transfer at infinite dialysate flow rates) were calculated for glucose, protein and uric acid and found to be complimentary to the results obtained by studies of solute equilibration. Possible reasons for the differences obtained are discussed.

Lymphatic drainage from the peritoneal cavity occurs mainly via the subdiaphragmatic stomata and significantly reduces net ultrafiltration and solute clearances during long-dwell peritoneal dialysis. Intraperitoneal cholinergic drugs constrict these stomata and may reduce peritoneal cavity lymphatic absorption. We evaluated ultrafiltration kinetics, solute transport, and lymphatic drainage during single hypertonic exchanges in rats using 2.5% dextrose dialysis solution with and without added neostigmine. Net ultrafiltration was enhanced in the neostigmine group (p less than 0.01) by a reduction in cumulative lymphatic absorption (p less than 0.01) and without an increase in total transcapillary ultrafiltration during the dwell time. Likewise solute clearances were significantly augmented with neostigmine primarily due to the increase in dialysate drain volume (p less than 0.01) since dialysate/serum solute ratios were unchanged. Pharmacological manipulation of peritoneal lymphatic absorption provides an alternative means of increasing the efficiency of long-dwell peritoneal dialysis without altering peritoneal transport of solutes and water.

We describe a continuous ambulatory peritoneal dialysis (CAPD) patient who developed failure of ultrafiltration for no apparent cause during the first year of treatment. Further investigation showed that peritoneal cavity lymphatic reabsorption during the dwell time exceeded cumulative transcapillary ultrafiltration and so caused negative net ultrafiltration. Peritoneal lymphatic drainage should be added to the list of causes that, either singly or in combination, lead to loss of ultrafiltration in CAPD.

This report of the NIH-supported National Continuous Ambulatory Peritoneal Dialysis (CAPD) Registry summarizes data on 7,404 patients treated with CAPD during the three-year period 1981 through 1983, or nearly one-half of patients treated in the USA who were treated with CAPD during this time. While age and diabetes mellitus impact on mortality, they appear to have a limited influence on transfer or infection rate. There were 1.7 episodes of peritonitis, 0.7 exit site/tunnel infections, and 0.3 catheter replacements reported per patient year of observation. Patients averaged 10.2 hospital days per year for CAPD complications and 22.3 hospital days per year for all causes. Comparisons of these data with similar data reported for other therapies are subject to variations in the distribution of population and disease characteristics, as well as the length of the observation period.

Previous studies in dialysis coils have suggested decreases in diffusive transport with ultrafiltration. The present studies were designed to test whether increasing blood channel width, alterations in concentration gradients, or molecular sieving at high ultrafiltration rates might explain the phenomenon. Increases in blood channel width and molecular sieving can account only in part for the decreases in diffusion observed. The results suggest that ultrafiltration causes alterations in transmembrane concentration gradients from blood to bath presumably associated with solute accumulation on the bath side of the membrane or may alter bath flow kinetics. Increases in total dialysance with ultrafiltration would be even greater if decreases in diffusive transport could be prevented.

To see if oral dipyridamole increases peritoneal clearances in humans undergoing peritoneal dialysis, two types of double-blind clinical studies were undertaken. In a single-dose study, 7 patients were randomized to take dipyridamole or placebo early in a peritoneal dialysis with 2 L, hourly cycles; later in the same dialysis a crossover administration was studied. In a multidose study, 17 patients were randomized to take dipyridamole or placebo three times daily and clearance studies were performed on days 1, 4, and 8 during 2 L, hourly peritoneal dialysis cycles. Neither the single dose of dipyridamole or placebo significantly altered drainage volumes, clearances, or dialysate protein from control periods. In the multidose study, mean values on dipyridamole or placebo were not significantly changed from respective baseline predrug values. Mean values with dipyridamole and placebo usually were not significantly different. Dipyridamole did not appear to improve peritoneal clearances even with repeated ingestion.

Reduced peritoneal clearances of creatinine and urate were demonstrated repeatedly in a patient with scleroderma and a patient with diabetes mellitus. Urea clearances were not significantly different from usual values. The findings suggest decreased peritoneal membrane permeability and/or area (if urea clearance is flow limited). Clearances increased to usual values with intraperitioneal isoproterenol in the patient with diabetes. There was no effect of isoproterenol in the patient with scleroderma.

CAPD continues to show promise as a continuous internal portable dialysis technique. Although unknown long-term problems may develop, it would seem at this time to offer an acceptable form of chronic dialysis for many patients.

We have previously shown that polyanions can be utilized to achieve balanced removal of sodium and water during peritoneal dialysis. The excessive binding of potassium, calcium, and magnesium to anionic polymers proves undesirable. The present study was designed to demonstrate the reversibility of cation binding by using a polycation (polyethylenimine) as the osmotic agent, thus favoring the removal of undesirable excess phosphate anions via peritoneal dialysis. Polyethylenimine shows a measurable affinity for phosphorus when present as dialysate in an in vitro system simulating peritoneal dialysis. The polycation also stimulates ultrafiltration across the rat peritoneum when present in dialysate. The polymer is toxic to the rat and light microscopy reveals gross morphological tissue alterations of the visceral mesothelium and associated organs. We have demonstrated that a polycation can give ultrafiltration with enhanced removal of phosphate. Although the polymer we chose as a prototype is toxic to the rat, other polycations should be studied.

Peritoneal dialysis solutions contain glucose as an osmotic agent to obtain ultrafiltration. Due to rapid absorption, glucose does not sustain high ultrafiltration during long exchanges. Nonabsorbable polyanions might be effective as osmotic agents when suspended in electrolyte solution. Concentrations of freely diffusible ions should be in Gibbs-Donnan equilibrium with plasma electrolytes. The ideal proportion of diffusable to polymerbound cation concentrations is unknown. To obtain concentrations of free ions in equilibrium with plasma, it is assumed that the polymer solution dialyzed against a polyelectrolyte solution of the desired composition (with hydraulic pressure higher on the polymer side) will approach the same thermodynamic activity as the electrolyte solution. Subsequently, if transmembrane pressure is released, osmotic ultrafiltration will occur in proportion to the hydrostatic pressure applied during polymer solution preparation. Polyacrylate solution so prepared was compared with a commercial dextrose dialysis solution in an in vitro simulation of peritoneal dialysis. With dwell times up to 24 h, sustained ultrafiltration with polymer was observed, whereas, with dextrose, ultrafiltration ceased after 8 h. Concentrations of diffusible bivalent cations in polyacrylate were lower than intended due to avid polymer complexing; however, dextran sulfate solutions were developed to contain desired concentrations of diffusible electrolytes. The conclusion is that some polymer solutions might be useful in clinical settings when high sustained ultrafiltration is needed.

The influence of temperature and time on insulin adsorption to plastic peritoneal dialysis bags was evaluated. A dialysis bag (1.5% dextrose, 2 liters) was injected with 25-microCi insulin I 125 and gently mixed. This bag was then attached to another empty bag of the same type. Following a bag-to-bag transfer method, the amount of insulin adsorbed on the plastic bags was measured at 24 degrees C and 37 degrees C, and after a 12-hour warming period at 37 degrees C. Regular insulin was added to the system in 40-unit increments up to 280 units. Radioactivity in all of the samples was measured in a gamma counter. As the amount of regular insulin increased, the percentage of insulin adsorbed decreased at both temperatures. More insulin was bound at 37 degrees C than at 24 degrees C for all levels of insulin. Data calculated according to the Langmuir isotherm equation showed that the maximum possible values of adsorption to the system at 24 degrees C and 37 degrees C were 17.8 and 18.4 units, respectively. The affinity constants at 24 degrees C and 37 degrees C were 0.0039 and 0.0065, respectively. The influence of prolonged warming at 37 degrees C was minimal. At the usual dosage of insulin (below 40 units) prescribed to the majority of dialysis patients, less than 9% (3.5 units) is adsorbed onto the dialysis bags.

These studies suggest that lymphatic absorption reduces net ultrafiltration by significant amounts and plays a major role in the overall ultrafiltration kinetics. Intraperitoneal drugs which decrease lymphatic absorption may increase net ultrafiltration, drainage volume, and solute clearances. Decreases in net ultrafiltration with drugs that decrease lymphatic absorption may provide an alternative means to increase net ultrafiltration with less use of hypertonic dextrose exchanges.

It has been suggested that filtration pressure equilibrium could occur in peritoneal capillaries during peritoneal dialysis with very hypertonic exchanges. Rats were exposed to peritoneal dialysis solutions using 16 ml instillations, 30 minute cycles, and dextrose concentrations from 1.4 to 20 g%. There was a plateau in ultrafiltration per exchange at mean osmotic gradients above 360 mOsm/kg H2O near 12.5 ml/ex (0.42 ml/min). The findings are also compatible with filtration pressure equilibrium predictions at an effective capillary plasma flow of 0.84 ml/min and a filtration fraction near 50%. Studies with cardiovascular drugs (norepinephrine i.v., nitroprusside i.p., and dobutamine i.v.) showed no effects on the maximum ultrafiltration rates. This might indicate that flow is rather fixed because of known microcirculatory effects of solutions themselves.

Three years of clinical experience with continuous ambulatory peritoneal dialysis are summarized. Serum urea nitrogen, creatinine, hematocrit, nerve conduction velocity, calcium, inorganic phosphorus, serum proteins, and electrolytes have been maintained in acceptable ranges. Peritonitis, although reduced in incidence because of solutions in plastic bags and a new adapter, is still a problem. Excessive carbohydrate absorption, obesity, and high serum triglyceride concentrations may be long-term problems in some patients.

Peritoneal inulin clearance during peritoneal dialysis is a useful indicator of efficiency of removal of larger solutes. Peritoneal dialysis solutions usually contain high glucose concentrations that interfere with the chemical measurements of inulin concentration. In these studies, inulin recoveries in simple glucose and peritoneal dialysis solutions with three chemical methods were compared; all methods reportedly were subject to minimal glucose interference. The findings showed one method subject to minimal and predictable glucose interference in all solutions tested. For two methods, interference in peritoneal dialysis solutions exceeded that predicted from glucose alone; this unexpected interference was shown to most likely result from carmalized glucose subsequent to the routine autoclaving of peritoneal dialysis solutions.

Free nuclei of damaged leukocytes adhere to hemodialysis membranes. To see if the incidence of antibodies to nuclear antigens is increased in patients receiving hemodialysis, serums from 77 patients undergoing long-term dialysis for one to 66 months were assayed for antibodies to extractable nuclear antigen and native deoxyribonucleic acid (DNA) by hemagglutination technics. Serums from 300 other hospital patients (who did not have diseases known to be associated with antibodies to nuclear antigens) were assayed concurrently. Of the 77 dialysis patients, serums from 19 (25 per cent) were positive for one or both antibodies. Serums from only three (1 per cent) of the 300 other patients had detectable antibodies. The incidence was significantly higher (p less than 0.001) in dialysis patients suggesting the possibility of sensitization to nuclear antigens during hemodialysis.

In patients with chronic renal failure, NaHCO3 therapy may correct or prevent acidemia. It has been proposed that the NaHCO3 required will not result in clinically significant Na retention comparable to that from similar increases in NaC1 intake. In each of ten patients with chronic renal failure, creatinine clearance (Ccr) range 2.5-16.8 ml/min, on an estimated 10-meq Na and C1 diet, electrolyte excretion was compared on NaHCO3 vs NaC1 supplements of 200 meq/day. Periods of NaHCO3 and NaC1 (in alternate order for successive patients) lasted 4 days, separated by reequilibration to base-line weight. Mean +/- SEM excretion (ex) of Na, C1, and HCO3 and deltaCcr and deltaweight (day 4-1) are compared below for the 4th day of NaC1 vs. NaHCO3 intake. Mean Ccr +/-SEM on day 4 of NaC1 and NaHCO3 were 10.8 +/-1.6 and 9.0 +/-1.4 ml/min, respectively (P less than 0.02). Mean systolic blood pressure (but not diastolic) increased significantly on NaC1 (P less than 0.05). No significant blood pressure changes were seen on NaHCO3. Net positive HCO3 balance occurred on NaHCO3 as indicated above and reflected a rise in mean serum HCO3 from 19 to 30 meq/liter (day 1 vs. 4) (P less than 0.01). Mechanisms for the greater excretion of Na on NaHCO3 may relate to C1 wasting as noted above on low C1 intake and limited HCO3 reabsorptive capacity. Thus, Na excretion by day 4 was greater on NaHCO3 than on NaHCO3 did Na excretion near intake (210 meq/day).

Topical application of dialysis solution to the rat microcirculation causes a transient vasoconstriction for 2 to 3 min. We assessed the clinical importance of this vasoconstriction by developing a dialysis solution without vasoactive properties, as assessed in the microcirculatory laboratory. The solution was of similar composition to human extracellular fluid. We tested its effects on Cur, Ccr, Cin, and dialysate protein concentration. We found that compared to commercial solutions, the lower osmolality of the NVS resulted in loss of ultrafiltration and decreases in clearance of urea and creatinine. The clearance of inulin was unchanged, and dialysate protein increased, suggesting a major increase in diffusive transport of large solutes. Increased diffusive transport of large solutes with NVS suggests that initial vasoconstriction seen in the rat could be present and clinically important during peritoneal dialysis in humans.

A patient developed a right pleural effusion soon after starting a program of continuous ambulatory peritoneal dialysis. The etiology of the effusion was unclear. 99mTc-labelled macroaggregated albumin was administered intraperitoneally, followed by 2 liters of dialysate. Trans-diaphragmatic leakage was clearly demonstrated, and confirmed by high count rates of pleural fluid with negligible blood count. This method can safely be used to demonstrate trans-diaphragmatic fluid leakage in peritoneal dialysis patients.

Two sodium dextran sulfates (DS) were investigated as possible osmotic agents for use in peritoneal dialysis using an in vitro model. Initial studies with a medium molecular weight DS (Mn = 4.000) showed that sodium clearances were higher than water clearances and that both are linear functions of the concentration of polymer. In another series of studies using a low molecular weight DS (Mn = 5,000), it was found that sodium clearances decrease linearly as sodium chloride (NaCL) is added to the initial dialysate solution with only a slight increase in ultrafiltration. By plotting sodium clearances and water clearances as functions of added NaCl at constant polymer concentration, the point at which sodium clearance and water clearances are equal can be determined and, at that point, isonatric contraction can be demonstrated in the vitro model.

Patterns of recurrent peritonitis episodes were examined in 6,335 new continuous ambulatory peritoneal dialysis (CAPD) patients entered into the National CAPD Registry. Forty-six percent of all peritonitis episodes were initial occurrences, with 8% of the patients reporting four or more episodes. The proportion of gram-positive and gram-negative infections was constant across episodes. In patients with multiple infections, negative organisms were found to have increased risk of recurring as gram-negative infection. A similar observation was made for fungal infections. Of patients with multiple peritonitis episodes, more than 40% of those who transferred to other maintenance renal replacement therapy identified peritonitis as the reason for transfer. A discrete time logistic model was used to estimate peritonitis risk in 4-month follow-up periods. Patients like those on the registry are estimated to have a 22% risk of developing peritonitis during any 4-month period. This risk was increased 4% for patients aged less than 21 years, 7% for nonwhite patients, and 19% in the period following a peritoneal infection.

The contribution of peritoneal cavity lymphatic absorption to ultrafiltration kinetics and solute clearances in continuous ambulatory peritoneal dialysis was evaluated in patients with normal (group 1) and high (group 2) peritoneal permeability X area during 4-h exchanges using 2 liters 2.5% dextrose dialysis solution with 30 g added albumin. Cumulative lymphatic drainage in all continuous ambulatory peritoneal dialysis (CAPD) patients averaged 358 +/- 47 ml per 4-h exchange and reduced cumulative net transcapillary ultrafiltration at the end of the exchange by 58 +/- 7.2%. The peak ultrafiltration volume was observed before osmotic equilibrium between serum and dialysate was reached and occurred when the net transcapillary ultrafiltration rate had decreased to equal the lymphatic absorption rate. Thereafter the lymphatic absorption rate exceeded the net transcapillary ultrafiltration rate, and intraperitoneal volume decreased. Extrapolated to 4 X 2 liters, 2.5% dextrose, 6-h exchanges per d, lymphatic drainage reduced potential daily net ultrafiltration by 83.2 +/- 10.2%, daily urea clearance by 16.9 +/- 1.9%, and daily creatinine clearance by 16.5 +/- 1.9%. Although lymphatic absorption did not differ between the two groups, lymphatic drainage caused a proportionately greater reduction in net ultrafiltration in group 2 (P less than 0.025), because these patients had more rapid dialysate glucose absorption (P less than 0.05) and less cumulative transcapillary ultrafiltration (P less than 0.01). These findings indicate that cumulative lymphatic drainage significantly reduces net ultrafiltration and solute clearances in CAPD and that ultrafiltration failure in CAPD occurs when daily lymphatic absorption equals or exceeds daily transcapillary ultrafiltration. Reduction of lymphatic absorption may provide a means for future improvement in the efficiency of CAPD.