Pharmacokinetics of once daily intraperitoneal cefazolin in continuous ambulatory peritoneal dialysis patients

This study determined the pharmacokinetic characteristics of once daily intraperitoneal (IP) cefazolin in continuous ambulatory peritoneal dialysis (CAPD) patients. Each of the 10 volunteer CAPD patients without active peritonitis received a single IP dose of 1 g of cefazolin sodium for a 6-h dwell. All patients underwent a fixed CAPD regimen comprising a first 6-h dwell followed by two 3-h dwells and a final 12-h overnight dwell. Blood and dialysate samples were collected at 0, 0.5, 1, 2, 3, 6 (end of first dwell), and 24 h after the administration of IP cefazolin. Any urine produced was collected over the 24-h study period. A validated HPLC method was used to analyze cefazolin in plasma, dialysate, and urine. The bioavailability was found to be 77.9 +/- 3.1%, volume of distribution 0.20 +/- 0.05 L/kg, and plasma half-life 39.9 +/- 25.4 h. Mean total, renal, and peritoneal clearances were 4.5 +/- 2.3, 1. 4 +/- 1.1, and 3.5 +/- 1.8 ml/min, respectively. Mean plasma and dialysate concentrations at 24 h were 42.8 +/- 14.3 and 31.8 +/- 11. 7 mcg/ml, respectively, well above the minimum inhibitory concentrations (MIC) of susceptible organisms. A once daily IP cefazolin dose of 500 mg/L gave desirable pharmacokinetic attributes for use as a suitable alternative to vancomycin for empiric treatment of CAPD-associated peritonitis.     

Treatment of gram-positive peritonitis with two intraperitoneal doses of vancomycin in continuous ambulatory peritoneal dialysis patients

Eight patients with end-stage renal failure on continuous ambulatory peritoneal dialysis (CAPD), who developed peritonitis, received an intraperitoneal dose of vancomycin (30 mg/kg body weight) with 6 h of peritoneal dwell and then resumed their routine CAPD schedule. Vancomycin concentration in serum, peritoneal dialysate (PD) from an overnight dwell and 1, 2 and 3 h after a new exchange was measured at 48 h (in 5 patients) and 7 days (in 6 patients). Except for an occasional 1-hour peritoneal fluid sample on the 7th day, all samples had satisfactory vancomycin levels. Five of the 8 patients who had gram-positive peritonitis and 1 with 'sterile' peritonitis received another similar intraperitoneal dose of vancomycin at the 7th day. All of these patients had good therapeutic response with a negative PD culture 3 weeks after the cessation of therapy and no relapse of infection in at least 1 month of follow-up. We conclude that 2 intraperitoneal doses of vancomycin (30 mg/kg body weight) given 1 week apart with 6 h of intraperitoneal dwell is an effective and adequate treatment for gram-positive and 'sterile' peritonitis in CAPD patients.     

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis

Eight adult patients without peritonitis maintained on chronic ambulatory peritoneal dialysis (CAPD) were administered a single oral dose of 320 mg trimethoprim (TMP) and 1600 mg sulfamethoxazole (SMX) to characterize the pharmacokinetics of TMP and SMX. Ten blood samples were drawn following the dose. TMP and SMX-active (SMXA) concentrations were quantified in serum and dialysate. The half-life of TMP and SMXA determined by model independent methods were 33.7 +/- 10.5 h (mean +/- SD) and 13.8 +/- 2.2 h respectively. Total body clearance of TMP was 32.8 +/- 10.1 ml/min and SMXA was 21.9 +/- 6.4 ml/min. CAPD clearance of TMP was 2.27 +/- 0.81 ml/min and SMXA was 1.72 +/- 0.93 ml/min. The average peritoneal dialysate concentrations over the 72-hour collection period of TMP and SMXA were 0.9 +/- 0.1 mg/l and 5.3 +/- 0.8 mg/l respectively. A dose of 320 mg TMP and 1600 mg SMX every 48 hours is recommended for CAPD patients with mild to moderate systemic infections.     

Treatment of peritonitis in APD: pharmacokinetic principles

Clinicians treating peritoneal dialysis (PD)-associated peritonitis should be aware that continuous ambulatory PD (CAPD) and automated PD (APD) have different effects on the pharmacokinetics of antibiotics. Results from various APD and comparative CAPD pharmacokinetic studies are reviewed. In APD patients, antibiotic half-lives were shorter during the cycler exchanges. Antibiotic peritoneal clearance was greater in patients treated with APD than those treated with CAPD regimens. Antibiotic clearance depends upon residual renal function and dialysate flow rate. To ensure that maximal antibiotic bioavailability occurs with intermittent intraperitoneal (IP) dosing, it is recommended that the antibiotic-containing dialysate must dwell at least 4 hours to ensure an adequate antibiotic depot in the body. Knowledge of antibiotic disposition in PD patients will assist clinicians in appropriate IP antibiotic dose selection and prevention of dose-related adverse effects.     

Peritoneal clearances with different dialysis regimens in children undergoing continuous cycling peritoneal dialysis

Peritoneal clearances and dialysate protein losses occurring in paediatric patients undergoing different continuous cycling peritoneal dialysis (CCPD) regimens have not been well defined. We, therefore, evaluated 10 children aged 15.8 +/- 2.5 (SD) years who were maintained on home peritoneal dialysis for 20.5 +/- 10 months. All patients had at least 3 months of CCPD. The patients were admitted to the Clinical Research Center for 48 hours and allocated to five different dialysis protocols. In protocol I, the frequency of exchanges was 10 per 10 hours; in Protocol II it was 5 per 10 hours; and in Protocol III it was 3 per 10 hours. Protocol II D and III D had, in addition, a daytime dwell of one-half the night-time volume. A 1.5% glucose dialysate solution was used for night-time dialysis, and 4.25% glucose dialysate solution for the daytime dwell. The mean inflow dialysate volume per exchange was 36.7 +/- 5.6 ml/kg body weight and was constant in each patient for each study protocol. BUN and creatinine clearances for each protocol were calculated and dialysate protein losses were measured. The data indicate that hourly night-time dialysis (Protocol I) provides best solute clearance. A daytime dwell further enhances the total solute clearance and should be used preferably in anuric patients. Residual urine output contributes significantly to the total solute clearance. Protein losses are maximum with low-frequency exchanges and a daytime dwell. No significant differences in the serum albumin concentrations were found during the different protocols; however, the long-term effect of the protein loss on the nutritional status of the patients requires further evaluation.     

Cefazolin plus netilmicin versus cefazolin plus ceftazidime for treating CAPD peritonitis: effect on residual renal function

BACKGROUND. The International Society for Peritoneal Dialysis (ISPD) treatment guidelines for continuous ambulatory peritoneal dialysis (CAPD) peritonitis 2000 recommended the use of cefazolin plus ceftazidime as the initial empirical therapy in patients with residual renal function (RRF). However, this treatment regimen has not been compared with the conventional regimen of cefazolin plus netilmicin in prospective, randomized controlled trials. METHODS: Stable CAPD patients who developed clinical evidence of peritonitis were randomized to receive intraperitoneal (i.p.) cefazolin plus netilmicin or cefazolin plus ceftazidime once daily in the long dwell for 14 days. For patients with RRF (>1 mL/minute) before entry into the study (N= 50), RRF and 24-hour urine volume were measured at days 1, 14, and 42 after commencement of i.p. antibiotic treatment. RESULTS: One hundred and two patients were recruited into the study. The primary cure rates of i.p. cefazolin plus netilmicin and cefazolin plus ceftazidime were 66.7% and 64.7%, respectively. The overall cure rate for the 2 treatment regimens was 82.3% for both. Seven patients (14%) from each treatment group required removal of the dialysis catheters due to treatment failure. Relapse of peritonitis occurred in 2 patients (4%) in both treatment groups. Thirty-six patients with RRF at baseline achieved primary cure of their peritonitis by the assigned antibiotics. In this subgroup of patients, their RRF and daily urine volume showed significant reduction at day 14 and returned to near baseline values at day 42. The degree of reduction in RRF and urine volume did not differ significantly between the patients treated with cefazolin plus netilmicin and cefazolin plus ceftazidime. CONCLUSION: Intraperitoneal cefazolin plus netilmicin and cefazolin plus ceftazidime have similar efficacy as empirical treatment for CAPD peritonitis. In CAPD patients with RRF, significant but reversible reduction in RRF and 24-hour urine volume could occur after an episode of peritonitis, despite successful treatment by i.p. antibiotics. The effect of i.p. cefazolin plus netilmicin, or i.p. cefazolin plus ceftazidime on RRF in CAPD patients with peritonitis does not appear to be different. Our findings do not support the routine use of cefazolin and ceftazidime as the empirical treatment for CAPD peritonitis.     

Down-regulation of CD43 molecule expression on intraperitoneal neutrophils in CAPD patients with peritonitis

To assess the release of proteases from neutrophils infiltrated into the peritoneal cavity in continuous ambulatory peritoneal dialysis (CAPD), we investigated the regulation of CD43, LAM-1 and Mac-1 expression on the neutrophil plasma membrane using FACS analysis in CAPD patients with peritonitis. Five CAPD patients with peritonitis and five CAPD patients without peritonitis were studied. CD43 expression was immunohistochemically determined in both groups of patients using flow cytometry, and comparisons were made between the two groups. Down-regulation of CD43 and LAM-1, and up-regulation of Mac-1 were demonstrated on neutrophils obtained from CAPD dialysate of peritonitis patients after 1-h dwell time. Further up-regulation of Mac-1 developed until a dwell time of 4 h. Immunoblot analysis for neutrophil lysate from dialysate showed the presence of the asialo form of CD43 molecules and their fragments, which may be produced by cleavage of the CD43 molecule at extracellular sites. The intraperitoneal neutrophils in dialysate from CAPD patients with peritonitis are continuously activated during dwell time, and proteases may be released from neutrophils into dialysate after only a short dwell time.     

Peritoneal sodium mass removal in continuous ambulatory peritoneal dialysis and automated peritoneal dialysis: influence on blood pressure control.

BACKGROUND/AIM: Sodium and water retention is common in peritoneal dialysis patients and contributes to cardiovascular disease. As peritoneal sodium removal depends partly on dwell time, and automated peritoneal dialysis (APD) often uses short dwell time exchanges, the aim of this study was to compare the 24-hour peritoneal sodium removal in APD and standard continuous ambulatory peritoneal dialysis (CAPD) patients and to analyze its possible influence on blood pressure control. METHODS: A total of 53 sodium balance studies (30 in APD and 23 in CAPD) were performed in 36 stable peritoneal dialysis patients. The 24-hour net removal of sodium was calculated as follows: M = ViCi - VdCd, where Vd is the 24-hour drained volume, Cd is the solute sodium concentration in Vd, Vi is the amount of solution used during a 24-hour period, and Ci is the sodium concentration in Vi. Peritoneal sodium removal was compared between APD and CAPD patients. Residual renal function, serum sodium concentration, daily urinary sodium losses, weekly peritoneal Kt/V and creatinine clearance, 4-hour dialysate/plasma creatinine ratio, proportion of hypertonic solutions, net ultrafiltration, systolic and diastolic blood pressures, and need for antihypertensive therapy were also compared between the groups. RESULTS: Peritoneal sodium removal was higher (p < 0.001) in CAPD than in APD patients. There were no significant differences in residual renal function, serum sodium concentration, urinary sodium losses, peritoneal urea or creatinine clearances, 4-hour dialysate/plasma creatinine ratio, or proportion of hypertonic solutions between groups. The net ultrafiltration was higher in CAPD patients and correlated strongly (r = 0.82; p < 0.001) with peritoneal sodium removal. In APD patients, peritoneal sodium removal increased significantly only in those patients with a second daytime exchange. The systolic blood pressure was higher (p < 0.05) in APD patients, and the proportion of patients with antihypertensive therapy was also higher in APD patients, although no significant relationship between blood pressure values and amount of peritoneal sodium removal was found. CONCLUSIONS: The 24-hour sodium removal is higher in CAPD than in APD patients, and there is a trend towards better hypertension control in CAPD patients. As hypertension control and volume status are important indices of peritoneal dialysis adequacy, our results have to be considered in the choice of the peritoneal dialysis modality.     

Pharmacokinetics of oral cephradine in continuous ambulatory peritoneal dialysis patients

Parenteral cephalosporins are widely used to treat peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Few data exist on oral antibiotics in treating this disease. This study examined the pharmacokinetics of oral cephradine in noninfected patients on CAPD. Assays for cephradine in dialysate and urine were performed by high-performance liquid chromatography. Following a 500-mg dose, the peak dialysate cephradine concentration was 8.7 +/- 1.4 micrograms/ml. The peak urinary concentration was 201 +/- 119 micrograms/ml. The maximum peritoneal clearance was 4.3 +/- 0.3 ml/min/1.73 m2. Dialysate cephradine concentrations were inadequate against Staphylococcus epidermidis and most gram-negative bacteria found in CAPD-associated peritonitis, but may be adequate for most strains of other gram-positive organisms causing this disease.     

The value of low-dose intraperitoneal immunoglobulin administration in the treatment of peritoneal dialysis-related peritonitis

BACKGROUND: Peritonitis is a major complication of continuous ambulatory peritoneal dialysis (CAPD). The value of immunomodulatory therapeutic approaches and, especially, methods aimed at augmenting opsonization in the treatment of peritoneal dialysis (PD)-related peritonitis is unclear. In this study, the effect of intraperitoneal (IP) immunoglobulin (Ig) usage, as an approach for strengthening opsonization, was evaluated in CAPD peritonitis. METHODS: The study included 24 patients with CAPD peritonitis. The patients were divided into two groups, A and B, each consisting of 12 patients. There were no significant differences between the groups in terms of age, gender, CAPD duration, and peritonitis rate. Empiric antibiotic treatment was a 2-week IP ampicillin+sulbactam/netilmycin combination. Group B was additionally given low-dose IP IgG (2 mL = 320 mg) with every exchange. The dialysate leucocyte counts were obtained in both groups until the number was <100 cells/microL to monitor the response to peritonitis treatment. RESULTS: In group A, the number of exchanges done until the dialysate leucocyte counts decreased to <100/mL was 13.9 +/- 1.4 and for group B 6.6 +/- 0.4 (p<0.001). The reduction in neutrophils was significantly faster in group B compared to group A (p<0.001). The number of exchanges until abdominal pain completely disappeared was 12.5 +/- 1.7 in group A and 5.6 +/- 0.7 in group B (p<0.001). CONCLUSIONS: The results of this study show that low-dose, continuous IP IgG administration in the treatment of PD-related peritonitis is safe and effective in shortening the treatment time.     

Plasma and dialysate immunoglobulin G in continuous ambulatory peritoneal dialysis patients: a multicenter study

Peritoneal dialysate immunoglobulin (Ig)G concentrations were measured in 120 continuous ambulatory peritoneal dialysis (CAPD) patients evaluated at four dialysis centers in different countries to assess the normal range for dialysate IgG and to investigate the relationships of this protein levels with peritoneal episodes, For 65 of these patients, plasma IgG levels were determined, and IgG clearances were calculated. The mean dialysate concentration of IgG was 6.9 +/- 4.2 mg/dl, and there was no difference between men and women or between patients who had or had not previously undergone hemodialysis. Dialysate IgG concentrations were significantly related to residual renal creatinine clearance and negatively correlated with dialysate volume, plasma albumin and total protein. There were no significant correlations between IgG levels in the dialysate and age, protein losses in the dialysate, time on CAPD or time from the last peritonitis episode. Plasma and dialysate IgG were unrelated to the incidence of peritonitis, statistical analysis being performed with different methods. These results suggest that IgG levels in the dialysate or plasma are not a major factor in the prevention of CAPD peritonitis.     

Specific characteristics of peritoneal leucocyte populations during sterile peritonitis associated with icodextrin CAPD fluids.

BACKGROUND: Icodextrin dialysate used for peritoneal dialysis contains an iso-molar glucose polymer solution, which provides sustained ultrafiltration over long dwell times and is considered a valuable approach to reduce intraperitoneal glucose exposure. However, several side effects have been described, including abdominal pain and allergic and hypersensitivity reactions. Also, reactions compatible with chemical peritonitis have been reported. Over the period of a few months (January 2002-May 2002), a remarkable increase in the number of continuous ambulatory peritoneal dialysis (CAPD) patients using icodextrin dialysate diagnosed with sterile peritonitis was observed in our unit. METHODS: Five of the CAPD patients using icodextrin dialysate in our unit and diagnosed with sterile peritonitis were screened for leucocyte count and leucocyte differentiation during a follow-up period of 77 +/- 23 days. In addition, expression of CD14, a receptor for lipopolysaccharide (LPS), on the peripheral and peritoneal monocyte population was analysed. These results were compared to CAPD patients suffering from bacterial peritonitis. RESULTS: The peritoneal leucocyte count of CAPD patients using icodextrin dialysate and diagnosed with sterile peritonitis did not decrease significantly before treatment with icodextrin dialysate was interrupted, whereas it currently disappeared within 2-4 days in proven bacterial peritonitis. The sterile, cloudy icodextrin effluent contained an excess of macrophages on the day of diagnosis, whereas in bacterial peritonitis essentially an increase in the granulocyte population was observed. No elevation in the eosinophil population was observed. In contrast to bacterial peritonitis, we observed no increase in CD14 expression on the peripheral and peritoneal macrophages on the day of presentation and during the follow-up period. CONCLUSIONS: Specific batches of the icodextrin CAPD fluids contain a macrophage chemotactic agent, which causes a sustained inflammatory state in the peritoneal cavity. Because no increase in the expression of the LPS receptor CD14 could be observed, the increased peritoneal leucocyte count is probably not caused by LPS or LPS-like (possibly peptidoglycan-like) contamination.     

Aluminum removal by peritoneal dialysis: intravenous vs. intraperitoneal deferoxamine

Aluminum removal via peritoneal dialysis was evaluated after the administration of deferoxamine in patients treated with CAPD and CCPD. The intravenous administration of deferoxamine, 40 mg/kg, led to a 730 +/- 139% increase in aluminum removal, compared to an increase of 641 +/- 178% after the drug was administered intraperitoneally. The mean dialysate: plasma concentration ratio for aluminum rose from 0.17 +/- 0.03 to 0.32 +/- 0.03 with intravenous deferoxamine administration, and from 0.19 +/- 0.05 to 0.38 +/- 0.07 with the intraperitoneal instillation of deferoxamine. In the seven patients with paired studies using both modalities of administration, there were no significant differences in the increments in plasma aluminum or in aluminum removal over a 24-hour period. In patients from whom effluent dialysate was collected for several days after the administration of deferoxamine, daily aluminum losses increased from 218 +/- 76 micrograms/24 hours before the administration of desferrioxamine to 1521 +/- 339, 1120 +/- 232, and 948 +/- 328 micrograms/24 hours over three successive days after deferoxamine. These data indicate that aluminum is effectively removed after the administration of either intravenous or intraperitoneal deferoxamine. The enhanced rate of removal of aluminum by peritoneal dialysis persists for several days after a single dose of deferoxamine. The efficacy and safety of long-term treatment with intraperitoneal deferoxamine requires further study.     

Peritoneal kinetics in children undergoing continuous ambulatory/cycling peritoneal dialysis

We present a report on peritoneal kinetics in children undergoing continuous ambulatory/cycling peritoneal dialysis (CAPD/CCPD). The effect of long-term treatment with CAPD/CCPD, peritonitis episodes, and dialysate inflow volume on peritoneal kinetics in children was evaluated. Peritoneal kinetic studies (PKSs) were performed in 47 pediatric patients at different times following initiation of CAPD/CCPD. In 18 of these patients, PKSs were repeated up to four times with an unchanged dialysate inflow volume after up to 55 months of CAPD/CCPD treatment. The PKS consisted of a 120-minute dwell with a 1.5% dextrose dialysate solution. Peritoneal clearance, dialysance, and dialysate to plasma (D/P) concentration ratios were calculated after 30, 60, and 120 minutes. The results of the serial PKSs demonstrate stable peritoneal creatinine and urea-N clearance, dialysance or D/P concentration ratios. Furthermore, there was no adverse effect of 32 peritonitis episodes. Finally, inflow volumes correlated directly with clearances of creatinine (P less than .01), urea-N (P less than .001), and potassium (P less than .001), and there was an inverse relationship to the D/P concentration ratios of creatinine (P less than .01), urea-N (P less than .01), potassium (P less than .01), and uric acid (P less than .01). Thus, CAPD/CCPD is a useful and effective long-term treatment modality for pediatric patients. Maximal dialysate inflow volumes should be provided to enhance peritoneal kinetics.     

Peritoneal defense in continuous ambulatory versus continuous cyclic peritoneal dialysis.

Several centers have reported a lower rate of peritonitis among adult patients on continuous cyclic peritoneal dialysis (CCPD) as compared to those undergoing continuous ambulatory peritoneal dialysis (CAPD). Preliminary results of our ongoing prospective randomized study comparing CAPD-Y with CCPD also suggest a lower peritonitis incidence among CCPD-treated patients. To investigate whether the two dialysis regimens could result in differences in local host defense, we studied peritoneal macrophage (PMO) function and effluent opsonic activity in eight patients established on CAPD-Y matched with eight chronic CCPD patients. Since short and long dwell times are inherent to both dialysis modalities, and we previously found that dwell time has an impact on PMO function and effluent opsonic activity, patients were studied after both a short (4 hr) and a long (15 hr) dwell time. In both groups PMO phagocytic capacity increased significantly with dwell time (39 +/- 3.3% at 4 hr vs. 58 +/- 4.2% at 15 hr in CAPD patients, and 40 +/- 3.9 vs. 72 +/- 3.3% in CCPD patients; P less than 0.01), as did PMO peak chemiluminescence response (31 +/- 4.9 vs. 77 +/- 7.2 counts.min-1/10(4) cells in CAPD, and 22 +/- 3.9 vs. 109 +/- 21.2 counts.min-1/10(4) cells in CCPD; P less than 0.01) and effluent opsonic activity (41 +/- 7.6 vs. 73 +/- 5.8% in CAPD and 39 +/- 6.2 vs. 70 +/- 5.9% in CCPD; P less than 0.01). However, no significant difference was found in either variable between CAPD and CCPD patients when dwell times were equal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Middle molecule and small protein removal in children on peritoneal dialysis

BACKGROUND: Dialysis efficiency has a great influence on the outcome of patients. Few data are available on the removal of solutes with molecular weights higher than urea and creatinine. The aim of our study was to assess the transport and the removal of substances with molecular weights up to 15 kD and to evaluate the contribution of residual renal function in peritoneal dialysis (PD) children. METHODS: Seventeen patients of 12 +/- 4 years undergoing automated PD were studied. Ten patients had 563 +/- 355 mL/day of urine output, and 7 were anuric. During a standardized nightly intermittent PD (NIPD) session, a single-injection inulin clearance was performed. Urea, creatinine, inulin (measured by HPLC), cystatin C and beta2-microglobulin (beta2m) were measured in blood, urine and dialysate. Clearances (L/week/1.73 m2) and weekly solute removal index (SRI) were calculated for all the solutes; weekly Kt/V was calculated for urea. RESULTS: In non-anuric versus anuric patients the total clearances were: urea 82.6 +/- 18.3 versus 71.3 +/- 26.4; creatinine 82.7 +/- 28.6 versus 47.8 +/- 18.8; inulin 42.8 +/- 11.3 versus 32.8 +/- 20.4; beta2m 14.2 +/- 13.8 versus 9.2 +/- 8.3; cystatin C 20.2 +/- 9.4 versus 9.7 +/- 4.8. In the patients with residual diuresis, the urea was removed mainly by PD (69.2%), while inulin, beta2m and cystatin C were removed by renal clearance (64.0%, 79.5% and 62.8%, respectively). Total, peritoneal and renal weekly Kt/V values in the subjects with residual renal function, were 2.86 +/- 0.70, 1.99 +/- 0.40 and 0.87 +/- 0.43, respectively. Peritoneal weekly Kt/V in the anuric patients was 2.36 +/- 0.85; total weekly Kt/V in the total group was 2.65 +/- 0.78. Weekly SRIs in non-anuric versus anuric patients were: urea 2.56 +/- 0.58 versus 2.09 +/- 0.74; creatinine 2.66 +/- 0.73 versus 1.46 +/- 0.56; inulin 2.36 +/- 0.92 versus 1.64 +/- 1.60; beta2m 1.26 +/- 1.10 versus 1.20 +/- 1.90; cystatin C 1.72 +/- 0.83 versus 1.58 +/- 1.62. CONCLUSIONS: Solutes removed during PD tend to decrease following an increase in molecular weight of the substance. Since anuric patients are at higher risk of middle molecule and small protein accumulation, more attention should be paid to the removal of middle molecules. Further studies should be undertaken to evaluate whether removing them has a clinical impact and to determine their threshold levels.     

Peritoneal clearance of leptin in continuous ambulatory peritoneal dialysis.

Leptin is a 16-kd protein that increases energy expenditure and limits food intake. Serum leptin (S-leptin) is elevated in dialysis patients, and little data have been reported on leptin clearance (Cl) during dialysis. We analyzed the peritoneal dialysis (PD) Cl of leptin in 15 continuous ambulatory peritoneal dialysis (CAPD) patients and compared the results to beta(2)-microglobulin (beta(2)-m), urea, and creatinine PD Cl. S-leptin was significantly elevated (Kruskal-Wallis, P < 0.005) in CAPD women (58.4 +/- 42.4 [SE] microg/L, n = 5) as compared with CAPD men (13.9 +/- 7.1, n = 10) and with healthy women (11.0 +/- 1.4, n = 13) and men (5.1 +/- 0. 9, n = 14). Correlations were found between percent of fat mass and S-leptin (P < 0.05); between S-leptin and the 24-hour PD leptin (P < 0.05); and between dialysate-to-plasma (D/P) beta(2)-m and D/P leptin (P < 0.01). PD leptin Cl (1.80 +/- 0.43 mL/min/1.73 m(2)) was higher than beta(2)-m Cl (1.22 +/- 0.31) (P < 0.01), but reduced as compared with urea Cl (8.84 +/- 1.20) (P < 0.005) and creatinine Cl (7.71 +/- 0.99) (P < 0.005). These results indicate that leptin is eliminated through the peritoneum membrane. However, peritoneal leptin clearance, as beta(2)-m, appears to be clearly restricted as compared with peritoneal transport of smaller molecules. Hence, leptin could use the same diffusion transport pathway as beta(2)-m. In addition, leptin, which has a higher molecular weight than beta(2)-m, was significantly more eliminated into the peritoneal dialysate. More studies are necessary to clarify whether this is an active leptin elimination process by peritoneal secretion or by a different restriction coefficient of diffusion through the peritoneum membrane.     

The effect of peritonitis on the transperitoneal transport of cefuroxime in patients on CAPD treatment

The pharmacokinetics and transperitoneal transport of cefuroxime were investigated in CAPD patients without peritonitis (n = 6), receiving 500 mg of the drug intravenously (i.v.) and intraperitoneally (i.p.) on separate occasions. CAPD patients with peritonitis were also investigated after i.p. administration of an initial dose of 500 mg cefuroxime followed by repeated doses of 250 mg. Routine hospital CAPD procedures and dwell-time schedules were followed during the study, and frequent blood and dialysate samples were collected. Cefuroxime was analysed by HPLC methods, and pharmacokinetic parameters were calculated. In the patients without peritonitis, the following pharmacokinetic parameters after i.v. and i.p. administration did not differ significantly (mean +/- SD): elimination half-life, 15.1 +/- 1.9 h; apparent volume of distribution 27.9 +/- 2.91; and total clearance, 21.5 +/- 1.2 ml/min. In contrast, the transperitoneal transport of cefuroxime differed significantly in the three studies. After i.v. administration the apparent transperitoneal clearance was low and time dependent, ranging from 4.2 +/- 1.2 to 1.4 +/- 0.4 ml/min. After i.p. administration the apparent transperitoneal clearance increased to 10.9 +/- 2.4 ml/min, whereas in the peritonitis patients a further increase to 21.5 +/- 3.5 ml/min was observed. In all patients we found cefuroxime concentrations in serum and dialysate, greatly exceeding MIC values of most pathogens involved in CAPD peritonitis and other systemic bacterial infections.     

Single UK centre experience on the treatment of PD peritonitis--antibiotic levels and outcomes.

BACKGROUND: There are few studies of the pharmacokinetics of vancomycin and gentamicin in peritoneal dialysis (PD) patients and the influence of antibiotic concentrations on treatment outcome. Concerns about resistance to ceftazidime and potential of aminoglycoside toxicity make the choice of empiric antibiotic difficult. METHODS: We retrospectively collected data from 613 patients on PD between 1 June 2002 and 31 December 2005. During this time, we adopted a protocol that minimized aminoglycoside exposure to patients with residual renal function and carefully monitored serum antibiotic concentrations. RESULTS: There were no statistical differences in mean day-5 vancomycin concentrations for continuous ambulatory peritoneal dialysis (CAPD) vs automated peritoneal dialysis (APD) and for anuric vs not-anuric patients. However, low levels (<12 mg/l) were recorded for 12.8% CAPD and 15% APD patients. These remained low at day 10 in 16% patients (25% if not anuric) despite incremental dosing. Vancomycin concentration did not predict cure or relapse of Gram-positive or culture-negative peritonitis. Gentamicin concentration (>2 mg/l in >50% patients) did not predict outcome of Gram-negative and culture-negative peritonitis. Moreover, cure rates were the same irrespective of whether gentamicin was continued for 14 days or was switched to ceftazidime after 5 days. CONCLUSION: We have confirmed that the International Society for Peritoneal Dialysis (ISPD) dosing guideline for vancomycin in CAPD and APD patients produces adequate serum concentrations of the antibiotics in the vast majority. However, large incremental dosing of vancomycin is needed if day-5 levels are low; especially for not-anuric patients. Whilst evidence of gentamicin toxicity in PD remains controversial, ISPD dosing regimen resulted in high levels for >50% patients. High gentamicin concentrations did not correlate with treatment success, but switching gentamicin to ceftazidime at day 5 appeared safe and limited aminoglycoside exposure. Increasing vancomycin and gentamicin concentrations do not appear to improve cure rates and alternative strategies (such as combination treatment) should be considered for future research.     

Inhibition of cytokine synthesis by peritoneal dialysate persists throughout the CAPD cycle.

The current study focused on the effect of continuous ambulatory peritoneal dialysis (CAPD) dialysate obtained following different intraperitoneal dwell periods on the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) from mononuclear leukocytes (PBMC). Aliquots of 5 x 10(6)/ml healthy peripheral PBMC were exposed to fresh or spent CAPD dialysate (10-240 min of intra-peritoneal dwell) and stimulated with Escherichia coli endotoxin (10 micrograms/ml, 2h). IL-6 and TNF alpha in cell supernatants were determined by specific enzyme immunoassays. Control PBMC in physiological buffer released 361 +/- 70 pg/ml IL-6 and 717 +/- 147 pg/ml TNF alpha (mean +/- SEM, n = 8), whereas exposure to fresh dialysis fluids severely suppressed cytokine release from PBMC (less than 30 pg/ml IL-6 and less than 15 pg/ml TNF alpha). A significant inhibition of IL-6 and TNF alpha release was also observed in PBMC exposed to spent dialysate. The inhibitory capacity of the spent fluids was pronounced with increasing intra-peritoneal dwell time (10 min: 183 +/- 45 pg/ml IL-6 and 538 +/- 109 pg/ml TNF alpha; 240 min: 26 +/- 5 pg/ml IL-6 and 105 +/- 30 pg/ml TNF alpha; mean +/- SEM, n = 16). These data indicate that the impairment of cell responsiveness following exposure of PBMC to peritoneal dialysate is not restricted to the unused fluids, but is also observed following intra-peritoneal equilibration. Moreover, our findings suggest the presence of cytokine inhibitory factors in the peritoneal dialysate of CAPD patients which appear to accumulate in the peritoneal effluent during the CAPD cycle.