Amphotericin selectively increases peritoneal ultrafiltration

Because amphotericin B is known to affect transport rates across biologic membranes, the effects of this agent on transport parameters in an animal model of peritoneal dialysis were investigated. When amphotericin B in doses ranging from 0.5 to 25 mg/kg was instilled intraperitoneally with commercial dialysis solution, diffusive clearances of phosphate and urea did not differ from control values measured in the same animals, and only a modest increase in potassium clearance was detected. Ultrafiltration due to the osmotic gradient induced by the dextrose content of the dialysis solution increased significantly to 0.31 mL/kg/min with amphotericin B, compared with control values of 0.18 mL/kg/min. The drug did not affect dextrose transport and the osmotic gradient did not differ in the two groups. Hence, the ultrafiltration coefficient was higher with amphotericin B (14 microL/kg/min/mosm), than during control dialyses (6 microL/kg/min/mosm). Increased water flux was detected at the lowest dose and there was no dose relationship over the range studied. Amphotericin B may be the type of agent that will be clinically useful in patients with reduced peritoneal ultrafiltration capacity, and safer analogues should be explored.     

The mechanism of dextrose-enhanced peritoneal mass transport rates

The mechanism whereby hypertonic dextrose affects peritoneal transport was investigated in a short-term model of peritoneal dialysis using alert intact rabbits. During control (1.5% dextrose) dialyses osmotic ultrafiltration was 0.28 mg/kg/min, the clearance of potassium was 0.98, urea 0.54, phosphate 0.32, and dextrose (reverse) 0.21 ml/kg/min. With 4.25% dextrose, the ultrafiltration rate increased to 0.73 ml/kg/min (P less than 0.02), but solute transport did not increase despite the added convective flux. The posthypertonic exchanges did not differ from control despite the effect of residual dialysate contaminating this peritoneal lavage. By indicator dilution residual volume averaged 12% of total dialysate volume. Acute volume expansion by intravenous dextrose after desoxycorticosterone acetate (DOCA) pretreatment increased the ultrafiltration coefficient, potassium and urea clearances significantly, and DOCA alone was ineffective. It is suggested that in uremic humans hypertonic dextrose dialysis increases peritoneal mass transport rates because the absorbed dextrose causes extracellular volume expansion that cannot be eliminated promptly. No evidence of a direct effect of dextrose augmenting peritoneal permeability was detected.     

Kinetics of peritoneal dialysis in children: role of lymphatics

Intraperitoneal fluid is absorbed continuously by convective flow into the peritoneal cavity lymphatics. We evaluated the role of lymphatic absorption in the kinetics of peritoneal dialysis during standardized four hour exchanges in six children using 40 ml/kg of 2.5% dextrose dialysis solution. Cumulative lymphatic absorption averaged 10.4 +/- 1.6 ml/kg and reduced the total net transcapillary ultrafiltration during the dwell time by 73 +/- 10%. Due to the considerable lymphatic absorption rate, maximum intraperitoneal volume was observed before osmolar equilibrium. Extrapolated to four study exchanges per day, lymphatic absorption decreased the potential daily drain volumes in the children by 27 +/- 5% and daily peritoneal urea and creatinine clearances by 24 +/- 4% and 22 +/- 5%, respectively. Compared with four hour exchanges using two liters of 2.5% dextrose dialysis solution in 10 adult CAPD patients with average peritoneal transport, the children had more rapid equilibration of urea, greater absorption of dialysate glucose, higher lymphatic absorption and lower net ultrafiltration (P less than 0.01 to P less than 0.05). Lymphatic absorption therefore causes a relatively greater reduction in net ultrafiltration and solute clearances in children than in adults.     

Dioctyl sodium sulphosuccinate increases net ultrafiltration in peritoneal dialysis

Background. The surface-active substance dioctyl sodium sulphosuccinate (DSS) has been reported to increase the peritoneal clearances of urea and creatinine. This study investigated the effects of DSS on the fluid and solute transport characteristics of the peritoneum. Design. A 4-h single-dwell experiment session of peritoneal dialysis using 25 ml of 3.86% glucose dialysis solution with an intraperitoneal volume maker was performed in 16 male Sprague-Dawley rats. In eight rats, 0.005% (50 p.p.m.) DSS was added to the dialysis fluid. No DSS was given to the other eight rats (control group). The transport of fluid, glucose, potassium, sodium, urea, phosphate and urate were analysed. Results. There was a significant increase in the intraperitoneal volume in the DSS group (33.0±2.9 ml) was significantly higher compared to the control group (28.8±2.1 ml. P<0.01). This increase in the drain volume was mainly due to a decrease in peritoneal fluid absorption rate in the DSS group (0.040±0.013 ml/min) as compared to the control group (0.054±0.010 ml/min, P0.05). There was no significant difference in the diffusive permeability and sieving coefficient for the small solutes between these two group. However, the clearances for urea and sodium were higher in the DSS group, mainly due to the increase in the dialysate volume. Conclusion. Our results suggest that DSS significantly increases the net ultrafiltration of peritoneal dialysis. This effect, which was mainly due to a decrease in the fluid absorption rate, contributed to the increased clearances for urea and sodium. DSS did not alter the diffusive permeability and sieving coefficient for the small solutes.     

Isoproterenol Enhancement of Peritoneal Permeability

As peritoneal dialysis is inefficient enough to be time-consuming and sometimes clinically ineffective, we have evaluated pharmacologic enhancement of peritoneal permeability. Peritoneal dialyses were performed in New Zealand white rabbits by instillation of 50 ml/Kg of isotonic dialysis solution of standard composition. Mean peritoneal clearance of creatinine was 0.60 ml/Kg/min and urea was 0.80 ml/Kg/min, each decreasing as intraperitoneal dwell was prolonged (by. 011 ml/Kg/min or less). With 0.04 uMl/Kg of isoproterenol administered intraperitoneally, clearances increased to 0.91 and 1.30 ml/Kg/min (p <0.01). When isoproterenol was added to the dialysis solution one hour or more before instillation, the increment in clearances was less. Instillation of dialysis solution 24 hours after addition of a higher dose of isoproterenol (0.2 uM/Kg) did not increase clearances above control. No effect of isoproterenol on bulk flow of water, associated with the osmotic effect of dextrose, was demonstrated. As peritoneal clearances increased, the ratio creatinine clearance : urea clearance did not decrease, consistent with increased peritoneal permeability as well as blood flow.     

Peritoneal dialysis in rabbits. A study of transperitoneal theophylline flux and peritoneal permeability

Since vasodilators can restore toward normal the decreased peritoneal clearances associated with vascular disease, the influence of aminophylline on peritoneal solute transport was studied in unanesthetized rabbits. Mean control creatinine clearance was 0.56 ml/kg/min and urea clearance 0.80 ml/kg/min. Neither intraperitoneal nor intravenous aminophylline increased peritoneal clearances, nor did the ratio creatinine clearance/urea clearance change from the control value, 0.70. Bidirectional flux of theophylline occurred at clearances of 0.70 ml/kg/min efflux and 0.64 ml/min influx. The removal rate of theophylline was 0.05% min, allowing therapeutic removal of excess aminophylline and warranting supplemental therapy during dialysis if therapeutic theophylline concentrations are required. As the intraperitoneal aminophylline was well tolerated, this route can be considered for therapeutic administration.     

Amphotericin B, mercury chloride and peritoneal transport in rabbits

BACKGROUND: The effect of glucose-induced ultrafiltration in peritoneal dialysis is dependent on the presence and function of ultrasmall transendothelial cell water channels. The mercury-sensitive aquaporin-1 was thought to represent these transcellular pores. Amphotericin B (ampho B) has been reported to increase ultrafiltration in both experimental and patient studies. The objective of this study was to investigate the hypothesis that intraperitoneal ampho B increases and mercury chloride inhibits aquaporin-1-mediated water transport in a chronic peritoneal dialysis model in the rabbit. MATERIAL AND METHODS: Eighteen female New Zealand White rabbits were included for peritoneal catheter implantation. Peritoneal transport parameters were determined in all rabbits by standard peritoneal permeability analysis (SPAR) with 3.86% glucose-based dialysis solution during a one-hour dwell prior the intervention SPARs, as a control. Ampho B (0.06 mg/kg body weight) was added to the dialysate for 3 (n = 9) or 5 consecutive days (n = 5) before investigation. Four rabbits were investigated after 3-day i.p. 0.6 mg/kg body weight ampho B. In 3 rabbits 0.06 mg/kg body weight liposomal ampho B was administered i.p. during 3 days before intervention SPAR. Fifteen rabbits were investigated during a one-hour dwell with 0.1 mM HgCl2 containing 3.86% glucose-based dialysis solution, while they were anesthetized. Three of these underwent in vivo fixation with glutaraldehyde prior to the HgCl2 SPAR to prevent toxic effects of mercury on peritoneal tissues. RESULTS: Intraperitoneal administration of ampho B did enhance the change in intraperitoneal volume during a one-hour dwell after 3-day i.p. treatment with the low dose (p < 0.02), but it did not affect peritoneal solute permeability. This was likely mediated by transcellular water channels, but not by aquaporin-1. No beneficial effects on the ultrafiltration were found with prolonged treatment or with the higher dose. Ultrafiltration decreased (8 ml/4 h to 1 ml/4 h, p < 0.03) after i.p. administration of HgCl2 with and without in vivo fixation, accompanied by a significant decrease in aquaporin-mediated water transport, estimated as the sieving of sodium (p < 0.001). Marked increases in the clearances of macromolecules were found after i.p. HgCl2 administration due to toxic effects: total protein clearance from 97 to 172 microl/min, p < 0.005, and albumin clearance from 59 to 158 microl/min, p < 0.005. These changes were less pronounced after in vivo fixation. CONCLUSION: Ampho B has likely no clinical relevance in treatment of ultrafiltration failure in PD patients. Aquaporin-mediated water transport could be inhibited and consequently ultrafiltration was reduced by i.p. administration of mercury chloride in our rabbit model.     

Prolonged intraperitoneal dwell decreases ultrafiltration coefficient in rabbits

In rabbits undergoing peritoneal dialysis, hypertonic (6% dextrose) dialysis solution increased the net ultrafiltration rate (UF) from 233 to 462 microL/kg/min, which was not proportional to the increment in the osmotic gradient, so the ultrafiltration coefficient decreased. As intraperitoneal dwell of hypertonic dialysate was prolonged, the gross and net UFs and ultrafiltration coefficients decreased, and the UF per dextrose absorption declined. The decrement in UF was multifactorial, including a component of fluid and solute stagnation, increasing the distance over which osmotic forces must exert their effects. Excessively hypertonic dialysis fluid should be used only briefly to achieve ultrafiltration efficiently and to avoid the high dextrose loading.     

Effect of chlorpromazine on peritoneal clearances

Chlorpromazine added to the dialysate improved the ultrafiltration and increased peritoneal clearances of urea and inulin. These results were postulated to be due to the narrowed stagnant dialysate fluid layer by the surface-active property of chlorpromazine. The study suggested another way to improve large solute (possibly uremic toxin) transport by using substances that facilitate convective transport. Intraperitoneal chlorpromazine increased the peritoneal dialysis efficiency.     

Pharmacological reduction of lymphatic absorption from the peritoneal cavity increases net ultrafiltration and solute clearances in peritoneal dialysis

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.     

Gentamicin removal during intermittent peritoneal dialysis

Gentamicin removal during intermittent peritoneal dialysis was studied in 13 uremic patients. The peak serum level after 80 mg of gentamicin intravenous drip was 6.00 +/- 1.3 micrograms/ml with a serum half-life of 13.6 +/- 4.07 h. The gentamicin dialysate level did not correlate with the corresponding serum concentration. The peritoneal gentamicin clearance (10.0 +/- 3.65 ml/min) correlated with the rate of protein loss, but not with the peritoneal clearances of urea and creatinine. When 4% glucose dialysate was used, the clearance of the drug increased considerably along with the ultrafiltration rate. Adding gentamicin (5 micrograms/ml) to the dialysate resulted in a sustained serum drug level. The mechanism of gentamicin transport through the peritoneal membrane is discussed. The study demonstrated significant removal of gentamicin during intermittent peritoneal dialysis.     

High peritoneal residual volume decreases the efficiency of peritoneal dialysis

BACKGROUND: Wide variation in peritoneal residual volume (PRV) is a common clinical observation. High PRV has been used in both continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis to minimize the time of a dry peritoneal cavity and to achieve better dialysis. However, the impact of PRV on peritoneal transport is not well established. In this study, we investigated the effect of PRV on peritoneal transport characteristics. METHODS: Peritoneal effluents were collected in 32 male Sprague-Dawley rats after a five-hour dwell with 1.36% glucose solution. Forty-eight hours later, a four hour dwell using 25 ml of 3.86% glucose solution and frequent dialysate and blood sampling was done in each rat with 125I-albumin as a volume marker. Before the infusion of the 3.86% glucose solution, 0 (control), 3, 6, or 12 ml (8 rats in each group) of autologous effluent (serving as PRV) was infused to the peritoneal cavity. RESULTS: After subtracting the PRV, the net ultrafiltration was significantly lower in the PRV groups as compared with the control group: 13.4 +/- 0.5, 12.0 +/- 1.0, 11.7 +/- 1.7, and 8.9 +/- 0.4 ml for 0, 3, 6, and 12 ml PRV groups, respectively (P < 0.001). The lower net ultrafiltration associated with higher PRV was due to (a) a significantly lower transcapillary ultrafiltration rate (Qu) caused by a lower osmotic gradient, and (b) a significantly higher peritoneal fluid absorption rate (KE) caused by an increased intraperitoneal hydrostatic pressure. No significant differences were found in the diffusive mass transport coefficient for small solutes (glucose, urea, sodium, and potassium) and total protein, although the dialysate over plasma concentration ratios values were higher in the high-PRV groups. The sodium removal was significantly lower in the PRV groups as compared with the control group (P < 0.01). CONCLUSION: Our results suggest that a high PRV may decrease net ultrafiltration through decreasing the Qu, which is caused by a decreased dialysate osmolality, and increasing the KE caused by an increased intraperitoneal hydrostatic pressure. The high volume of PRV also decreased the solute diffusion gradient and decreased peritoneal small solute clearances, particularly for sodium. Therefore, a high PRV may compromise the efficiency of dialysis with a glucose solution.     

Effects of gastrointestinal hormones on transport by peritoneal dialysis

Because the gastrointestinal hormones are known to dilate the splanchnic vasculature, their effects on transport of water and solutes during peritoneal dialysis were studied in an experimental model, the rabbit. In unanesthetized rabbits, dialysate volume was calculated by isotope dilution, and clearances were estimated by dialysate/plasma concentration ratio factored by minute volume. With isotonic dialysis solution, the mean increment in dialysate volume per minute of intraperitoneal dwell was 0.19 ml/kg/min, and mean clearances of creatinine and urea were 0.71 and 0.90 ml/kg/min, respectively. When administered intravenously, secretin significantly augmented osmotically induced water flux, but not when given intraperitoneally. Neither glucagon nor cholecystokinin affected dialysate volume. Intravenously, but not intraperitoneally, glucagon increased peritoneal clearances of creatinine and urea to more than 150% of control values. Neither cholecystokinin nor secretin augmented significantly peritoneal mass transport when given by either route. The data suggest that the site of acton is the endothelial surface of the membrane, that the mechanisms of augmenting transport involve increased permeability and/or surface area, and that agents which combine an increase in mass transport and capillary filtration coefficient may be clinically useful.     

Peritonfal Dialysis in the Treatment of Severe Hypercalcemia

A 56-year-old man with multiple myeloma and compromised renal function underwent peritoneal dialysis for the treatment of severe hypercalcemia. During dialysis, peritoneal clearances, of total calcium, unbound calcium, urea, and creatinine were assessed. Clearances of total calcium (4.8 ± 0.4 ml/min) and unbound calcium (7.8 ± 0.5 ml/min) were shown to vary directly with the clearances of urea (15.5 ± 1.3 ml/min) and creatinine (8.5 ± 0.8 ml/min). Despite relatively low clearances of all these solutes, during the period of 42 hours, 1,638 mg of calcium was removed in the dialy-sate and total serum calcium decreased from 17.6 mg/dl to 10.2 mg/dl. Our data indicates that peritoneal dialysis is an effective adjunct in controlling severe hypercalcemia and should be considered when other forms of therapy are inadequate.     

Effects of histamine and its receptor antagonists on peritoneal permeability

Peritoneal fluid and mass transfer rates were studied in rabbits undergoing control dialyses and dialyses with intraperitoneal histamine, or its receptor antagonists alone or in combination. These drugs had negligible effects on peritoneal ultrafiltration and small solute clearances. Histamine raised protein exudation from 1.6 to 2.9 mg/kg/min, an effect blocked by its antagonists which given alone did not lower protein loss. These data demonstrate the existence of histamine receptors in the peritoneal diffusion barrier and show that they do not control transport under baseline conditions, but can be blocked should abnormal histamine release occur. Increased peritoneal permeability with sterile peritonitis was unaffected by ranitidine, suggesting alternative mediators.     

Augmented Peritoneal Mass Transport with Intraperitoneal Nitroprusside

Lightly restrained, alert New Zealand white rabbits underwent peritoneal dialysis by percutaneous instillation of standard dialysis solution with or without intraperitoneal nitroprusside. Corrected to a mean intraperitoneal dwell time of 36 minutes, mean clearances of creatinine and urea were 0.74 and 0.90 ml/kg/min in six rabbits. With intraperitoneal nitroprusside, 1.13 mg/kg clearances increased to 1.13 and 1.30 ml/kg/min (p<0.01) respectively. The 53 percent increment in creatinine clearance maintained the ratio clearance larger/smaller solute suggesting increased peritoneal permeability and/or area. Lower nitroprusside doses were less effective and not significantly above control. Nitroprusside also increased clearances during hypertonic peritoneal dialysis, but had no effect on osmotically induced water flux. Lavage studies demonstrated a persistent effect of nitroprusside after a single exposure and a sustained effect with repeated use.     

Effect of intraperitoneal neostigmine on peritoneal transport characteristics in CAPD.

Lymphatics have been suggested to play a major role in the absorption of dialysate, which consequently affects the adequacy of peritoneal dialysis. Neostigmine has been found to decrease lymphatic absorption in rats, presumably by causing constriction of the lymphatic stomata. We investigated the effect of neostigmine on seven continuous ambulatory peritoneal dialysis (CAPD) patients in a prospective study. We performed modified peritoneal equilibration tests both with and without intraperitoneal neostigmine in a random order. Radiolabeled albumin (0.8 mg) was added to 2 liters of dialysate +/- 2.0 mg neostigmine. We evaluated ultrafiltration and creatinine, phosphate, and urea clearances. The dialysate bag and the peritoneum were scanned at the initiation and conclusion of the four-hour dwell period. We found no change in ultrafiltration, residual volumes, creatinine, phosphate and urea clearances, or albumin recovered. Of the seven patients exposed to neostigmine, four had diarrhea, abdominal cramps, nausea, and vomiting. In conclusion, we found that 2 mg i.p. neostigmine did cause significant side-effects and did not alter transport characteristics in CAPD patients.     

Influence of intraperitoneal gentamicin on peritoneal transport in IPD patients

We have investigated the effect of intraperitoneal gentamicin on dialysis efficiency in 10 intermittent peritoneal dialysis (IPD) patients. The following parameters were measured: net ultrafiltration (UF); concentration ratios (D/P) of urea, creatinine, potassium; peritoneal clearances (ml/min) of urea, creatinine, potassium; mass transfer of sodium (MT_Na); sodium sieving index (SC_Na). It has been found that gentamicin significantly decreased D/P urea (p<0.056) and D/P creatinine (p<0.05). We found also a significant decrease of mean clearances of urea (p<0.05) and creatinine (p<0.05). The mean clearance of potassium did not significantly change. There was no significant change in UF, MT_Na and SC_Na. Our preliminary data suggest that gentamicin decreases the permeability of the peritoneum for certain low molecules in IPD patients, which may have a negative impact on dialysis efficiency.     

Effect of hypertonic dialysate and vasodilators on peritoneal dialysis clearances in the rat

A model for performing peritoneal dialysis in the rat was established which permitted the consistent measurement of dialysis clearances. The effects on urea and inulin clearances of interperitoneal vasodilators and 4.25% dextrose were compared. Isoproterenol, nitroprusside, histamine, and bradykinin, when added to 1.5% dextrose dialysate for three consecutive exchanges, all produced approximately a 20% increase in urea and inulin dialysis clearances. These increases in clearances persisted in the three subsequent exchanges when no drugs were added to the dialysate. The addition of isoproterenol, nitroprusside, or histamine to six consecutive exchanges did not produce a further increment in clearances. The use of 4.25% dextrose dialysate for three exchanges produced approximately a 50% increase in urea and inulin clearances. Clearances remained about 35% greater than control values in the subsequent three 1.5% dextrose exchanges.     

Intraperitoneal atrial natriuretic peptide increases peritoneal fluid and solute removal

BACKGROUND: Atrial natriuretic peptide (ANP) is a hormone with well-known diuretic and vasodilating properties. Recently it was reported that ANP could increase the peritoneal fluid formation and increase peritoneal solute clearance. This study investigated the effect of ANP on peritoneal fluid and solute transport characteristics. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups. A four-hour dwell study using 25 mL 2.27% glucose dialysis solution with 50 microg/kg ANP (N = 6, H-ANP) or 5 microg/kg ANP (N = 6, L-ANP) or without ANP (N = 8, control) and frequent dialysate and blood sampling was done in each rat. Radiolabeled human albumin (RISA) was added to the solution as an intraperitoneal volume marker. RESULTS: The intraperitoneal volume was significantly higher in the H-ANP group as compared with the control group and the L-ANP group. The drainage volume was 26.2 +/- 1.1, 25.5 +/- 0.7, and 29.8 +/- 0.8 mL for the control, L-ANP, and H-ANP groups, respectively (P < 0.01). This was related to significant differences in the peritoneal fluid absorption rates (K(E); estimated as the RISA elimination coefficient): 39 +/- 3, 38 +/- 3, and 19 +/- 4 microL/min, and in the direct lymphatic absorption rate (K(EB); estimated as the clearance of RISA from dialysate to blood): 7 +/- 1, 6 +/- 1, and 4 +/- 1 microL/min for the control, L-ANP, and H-ANP groups, respectively (all P < 0.01). No differences were found in the intraperitoneal volume, K(E), and K(EB) between the control group and the L-ANP group. The diffusive mass transport coefficient (K(BD)) for urea, sodium, potassium, and total protein did not differ among the three groups. However, the glucose D/D(0) was significantly higher, and the K(BD) for glucose was significantly lower in the H-ANP group as compared with the other two groups. Solute clearances (+175% for sodium and +26% for potassium) were significantly increased in the H-ANP group, mainly as a result of the increased fluid removal in this group. CONCLUSIONS: Our results suggest that ANP may decrease peritoneal fluid absorption (by 51%, partially because of decreasing the direct lymphatic absorption), resulting in a significant increase in peritoneal fluid removal and small solute clearances. While the basic diffusive permeability of the peritoneal membrane was not changed, the peritoneal glucose absorption was retarded by adding ANP to peritoneal dialysate, perhaps through interaction of ANP with glucose metabolism.