Ubiquitin-activating enzyme (UBA1) is required for sperm capacitation, acrosomal exocytosis and sperm-egg coat penetration during porcine fertilization.

Protein ubiquitination is a stable, covalent post-translational modification that alters protein activity and/or targets proteins for proteolysis by the 26S proteasome. The E1-type ubiquitin-activating enzyme (UBA1) is responsible for ubiquitin activation, the initial step of ubiquitin-protein ligation. Proteasomal proteolysis of ubiquitinated spermatozoa and oocyte proteins occurs during mammalian fertilization, particularly at the site of sperm acrosome contact with oocyte zona pellucida. However, it is not clear whether the substrates are solely proteins ubiquitinated during gametogenesis or if de novo ubiquitination also occurs during fertilization supported by ubiquitin-activating and -conjugating enzymes present in the sperm acrosome. Along this line of inquiry, UBA1 was detected in boar sperm-acrosomal extracts by Western blotting (WB). Immunofluorescence revealed accumulation of UBA1 in the nuclei of spermatogonia, spermatocytes and spermatids, and in the acrosomal caps of round and elongating spermatids. Thiol ester assays utilizing biotinylated ubiquitin and isolated sperm acrosomes confirmed the enzymatic activity of the resident UBA1. A specific UBA1 inhibitor, PYR-41, altered the remodelling of the outer acrosomal membrane (OAM) during sperm capacitation, monitored using flow cytometry of fluorescein isothiocyanate-conjugated peanut agglutinin (FITC-PNA). Although viable and motile, the spermatozoa capacitated in the presence of PYR-41, showed significantly reduced fertilization rates during in vitro fertilization (IVF; p < 0.05). Similarly, the fertilization rate was lowered by the addition of PYR-41 directly into fertilization medium during IVF. In WB, high Mr bands, suggestive of protein ubiquitination, were detected in non-capacitated spermatozoa by antibodies against ubiquitin; WB with anti-phosphotyrosine antibodies and antibodies against acrosomal proteins SPINK2 (acrosin inhibitor) and AQN1 (spermadhesin) revealed that the capacitation-induced modification of those proteins was altered by PYR-41. In summary, it appears that de novo protein ubiquitination involving UBA1 contributes to sperm capacitation and acrosomal function during fertilization.

A multicenter study of noncompliance with continuous ambulatory peritoneal dialysis exchanges in US and Canadian patients.

Recent evidence suggested that noncompliance (NC) with continuous ambulatory peritoneal dialysis (CAPD) exchanges may be more common in US than in Canadian dialysis centers. This issue was investigated using a questionnaire-based method in 656 CAPD patients at 14 centers in the United States and Canada. NC was defined as missing more than one exchange per week or more than two exchanges per month. Patients were ensured of the confidentiality of their individual results. Mean patient age was 56 +/- 16 years, 52% were women, and 39% had diabetes. The overall admitted rate of NC was 13%, with a rate of 18% in the United States and 7% in Canada (P < 0.001). NC was more common in younger patients (P < 0.0001), those without diabetes (P < 0.001), and employed patients (P < 0.05). It was also more common in black and Hispanic than in Asian and white patients (P < 0.001). NC was more common in patients prescribed more than four exchanges daily (P < 0.0001) but was not affected by dwell volume. On multiple regression analysis, the independent predictors of NC, in order of importance, were being prescribed more than four exchanges per day, black race, being employed, younger age, and not having diabetes. Being treated in a US unit did not quite achieve significance as a multivariate independent predictor. These findings suggest that NC is not uncommon in CAPD patients and is more frequent in US than in Canadian patients. However, country of residence is less powerful as a predictor of NC than a variety of other demographic and prescription factors.

Pharmacokinetics of intraperitoneal epoetin alfa in patients on peritoneal dialysis using an 8-hour "dry dwell" dosing technique.

Pharmacokinetic studies of intraperitoneal (IP) epoetin alfa administered to continuous ambulatory peritoneal dialysis (CAPD) patients have shown low bioavailability, primarily attributable to the dilutional effect of coadministered dialysate. However, bioavailability is improved by instilling the dose into a dry peritoneum. The current study was designed to determine whether absorption after administration into a dry peritoneum is improved by extending the dry dosing period from 4 to 8 hours. The pharmacokinetics of a single 100-unit/kg IP epoetin alfa dose were studied in 8 noninfected CAPD patients. The dose was instilled into a dry peritoneum via the peritoneal catheter and allowed to dwell for 8 hours. CAPD was then resumed. Blood samples were collected for 96 hours after the dose. A 14-hour effluent dialysate sample was collected to determine epoetin alfa recovery. Enzyme immunoassay was used for epoetin alfa analysis of serum and effluent. Standard pharmacokinetic methods were employed for analysis of the serum concentration time data. The extent of epoetin alfa absorption was significantly greater than previously reported for a 4-hour dry dwell. The mean (+/-SD) dose-normalized area-under-the-curve (nlAUC(0-infinity)) using the 8-hour dry dwell dosing technique was 6,331 +/- 2,536 mIU. h/mL. This is significantly greater than the value of 2,589 +/- 1,450 mIU. h/mL (two-sided P value = 0.002) from a previous study in which patients received the same 100-unit/kg dose using a 4-hour dry dwell. The absorption of epoetin alfa administered by the intraperitoneal route is improved by extending the time the dose resides in a dry peritoneum.

Pharmacokinetics of quinupristin-dalfopristin in continuous ambulatory peritoneal dialysis patients.

Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.

Comparison of intraperitoneal and subcutaneous epoetin alfa in peritoneal dialysis patients.

OBJECTIVE: To compare the efficacy of intraperitoneal (i.p.) and subcutaneous (s.c.) administration of epoetin alfa in patients receiving peritoneal dialysis (PD). DESIGN: A 32-week prospective, randomized, cross-over experimental design. SETTING: Two university-based outpatient PD centers. PATIENTS: Twenty adult PD patients receiving stable doses of s.c. epoetin alfa enrolled in the study. Thirteen patients completed 32 weeks of follow-up. INTERVENTION: Patients were randomly assigned to receive either s.c. or i.p. epoetin alfa at the start of the study. Dose adjustments were made to maintain baseline hematocrit +/- 3 percentage points. Following 16 weeks of treatment, patients crossed over to the other route of administration for an additional 16 weeks. Intraperitoneal epoetin alfa was administered into an empty peritoneal cavity for approximately 8 hours before resuming dialysis. End-of-study i.p. epoetin alfa doses required to maintain target hematocrit were given twice weekly (n = 1), once weekly (n = 11), or once every other week (n = 1). All patients received iron supplements to maintain or exceed prestudy iron parameters. MAIN OUTCOME MEASURE: Prior to the study, the primary outcome measure was defined as the difference in epoetin alfa dose between i.p. and s.c. administration. RESULTS: Thirteen patients completed the study. The area under the dosing-requirement curve for i.p. epoetin alfa was larger than for s.c. administration (p = 0.0029), and the slope of the 16-week dose-requirement curve was greater for i.p. administration (p = 0.017), suggesting greater dose stability for s.c. administration. Paired analysis indicated greater i.p. intrapatient dose requirements (p < 0.0001). The mean difference in s.c. versus i.p. doses was 5000 +/- 1510 units per week. Some patients required escalating i.p. doses to maintain target hematocrit values. Iron administration and iron stores were similar in both groups. CONCLUSION: Intraperitoneal epoetin alfa may be a suitable alternative for some patients for whom s.c. dosing is undesirable. Large i.p. versus s.c. dosing differences noted in a few patients are unexplained, but may result from interpatient variability in i.p. epoetin alfa absorption. Intraperitoneal dosing into an empty peritoneum can be done safely and effectively.

Association between human recombinant EPO and peripheral vascular disease in diabetic patients receiving peritoneal dialysis.

Peripheral vascular disease is a serious and frequent problem in diabetic patients. Since the beginning of the widespread use of erythropoietin (EPO), we have noted an increase in peripheral vascular disease in diabetic patients receiving peritoneal dialysis and erythropoietin. This prompted us to study the effects of erythropoietin on peripheral vascular disease in patients receiving peritoneal dialysis. We retrospectively reviewed medical records of all diabetic patients in our program who received peritoneal dialysis from 1990 to 1996. Demographic and laboratory data as well as EPO use data were collected. Hospital days and occurrence of vascular events (defined as peripheral vascular surgery, amputation, or recommendation of vascular surgery or amputation by a vascular surgeon) were determined for diabetic patients receiving peritoneal dialysis. Comparisons were made between those who received EPO and those who did not received EPO, as well as comparing vascular events in 28 patients who received peritoneal dialysis before and after beginning EPO. Patients who received erythropoietin were found to have a significantly shorter time to a first vascular event, a greater number of vascular events, and more hospital days associated with vascular disease than diabetic patients who did not receive erythropoietin. With multivariate analysis, significant risk factors for the development of peripheral vascular disease in these patients were erythropoietin use, erythropoietin dose, and smoking. Twenty-eight patients who initially performed peritoneal dialysis without receiving EPO, and later received EPO, had a significant increase in vascular events, including amputations only while receiving EPO. We found the use of erythropoietin to be associated with peripheral vascular events in diabetic patients who receive peritoneal dialysis. Further investigation is warranted.

Characteristics of long-term peritoneal dialysis survivors: 18 years experience in one center.

OBJECTIVES: Long-term experience of patients on peritoneal dialysis (PD) in general, and in diabetic patients specifically, is limited. Few patients have been followed on PD for over 8 years. Our aim was to evaluate and characterize long-term survivors (LTS) on PD for more than 100 months. A retrospective analysis of 20 patients who survived on PD for more than 100 months was performed. Data on long-term survivors was compared to data of 103 patients who died or switched to hemodialysis (HD) in less than 100 months. DESIGN: The study included all patients starting PD prior to 1 January 1986. Demographic, biochemical, dialysis prescription, and morbidity data were obtained on these patients. Characteristics of long-term survivors on PD (more than 100 months), was compared with those who died or switched to HD in less than 100 months, using Student t-test. SETTING: An experienced single center, university-based dialysis program. PATIENTS: 165 patients started PD at the University of Wisconsin prior to 1 January 1986. Forty three had type I diabetes mellitus and 24 had type II diabetes mellitus as the cause of their renal failure. RESULTS: Twenty patients survived on PD more than 100 months (LTS). Long-term survival of type I diabetic patients was seen in 7 of 43 patients at risk. Seventeen type I diabetics received renal transplants and ten died. 103 patients either died or switched to HD in less than 100 months. Long-term survivors were significantly younger, weighed less, had fewer episodes of peritonitis, fewer hospital days, and were prescribed more dialysis per kg body weight, than those who died or switched to HD prior to 100 months. CONCLUSIONS: Long-term survival on CAPD for longer than 100 months is possible with survival periods up to 18 years in both males and females and in nondiabetics as well as patients with type I diabetes mellitus. No patient with type II diabetes mellitus survived longer than 100 months on CAPD. In comparison to short-term survivors, long-term survivors were characterized by being younger, weighing less, having fewer episodes of peritonitis, fewer hospital days, and were prescribed more dialysis/kg body weight.

Clinical pharmacokinetics during continuous ambulatory peritoneal dialysis.

Peritoneal dialysis (PD) has gained recognition worldwide as an alternative to haemodialysis in the management of patients with end-stage renal disease. Because the peritoneal catheter provides direct access to the peritoneum, intraperitoneal drug administration has become widely used for the administration of certain drugs. The instillation and drainage of PD fluids contribute to the total body clearance of drugs given by other routes. For most drugs, peritoneal clearance is low. This paper provides an updated review of recently published pharmacokinetic studies involving the administration of selected drugs to patients receiving PD. Antibiotics continue to be extensively studied and administered in PD patients because of the frequent occurrence of infections. Epoetin (recombinant human erythropoietin) has become widely used and is the subject of ongoing pharmacokinetic investigation. Intraperitoneal insulin has become accepted for the treatment of patients with diabetes receiving PD; the pharmacokinetics of vitamin D analogues in PD patients continue to be explored.

Long-term outcome of diabetic patients receiving peritoneal dialysis.

OBJECTIVE: Data from the United States Renal Data Systems (USRDS) suggest that older diabetic patients with end-stage renal disease will have improved survival if they receive hemodialysis versus peritoneal dialysis. Younger diabetic patients have equal survival on either treatment modality. To address more specifically the risk factors for long-term survival of diabetic patients receiving peritoneal dialysis, we analyzed the long-term outcome of 118 diabetics receiving peritoneal dialysis over a decade and compared them to 165 nondiabetic patients. DESIGN: Retrospective analysis utilizing the Cox proportional hazards model to identify risk factors for survival of both diabetic and nondiabetic patients. SETTING: An experienced, single-center, university-based dialysis program. PATIENTS: All patients receiving home peritoneal dialysis for at least one month from 1 January 1981 to 31 December 1990. Diabetics were classified as type I or type II, in addition to age stratification. Most type I diabetic patients used insulin via the intraperitoneal route. MAIN OUTCOME MEASURES: Patient survival and technique survival. RESULTS: The most significant risk factor for diabetic patient survival was diabetes type (relative risk type I to type II 0.14, p < 0.0001). On treatment serum albumin, predialysis blood urea nitrogen and predialysis serum cholesterol were also significant risk factors (p < 0.01). For nondiabetic patients, age, on treatment serum albumin, and current smoking were significant survival risk factors. Survival of patients 55 years or less was not significantly different between diabetic and nondiabetic patients. Survival of patients greater than 55 years was better in nondiabetic patients. CONCLUSION: These findings of a long-term follow-up period suggest a good survival for younger type I diabetic patients receiving peritoneal dialysis. Reasons other than age for the discrepancy in survival of young versus old diabetics receiving peritoneal dialysis should be sought.

Serum advanced glycosylation end-products in patients on hemodialysis and CAPD.

OBJECTIVES: Part I: To evaluate the long-term effects of daily glucose absorption from the peritoneal dialysis fluid on the formation of low-molecular-weight advanced glycosylation end-products (AGE-peptides) in nondiabetic continuous ambulatory peritoneal dialysis (CAPD) patients. Part II: To determine the acute effect of CAPD on serum AGE-peptide concentrations. DESIGN: Part I: Noninterventional, parallel, cross-sectional clinical trial. Part II: Crossover clinical trial. SETTING: A university-based hospital, and clinics. PATIENTS: Part I: Sixty nondiabetic subjects recruited into three age-matched (+/- 5 years) groups, as follows: 20 healthy volunteers (controls); 20 hemodialysis patients; and 20 CAPD patients. Part II: Eight patients with diabetes mellitus (type I or II) and chronic renal failure who were about to undergo CAPD. INTERVENTION: Part I: None. Part II: Uninterrupted CAPD, as medically required. MEASUREMENTS: Part I: To determine serum AGE-peptide concentrations blood samples were obtained randomly from controls and CAPD patients, and predialysis from hemodialysis patients. Hemoglobin A1c was also measured in all subjects. Part II: To determine serum AGE-peptide concentrations, blood samples were collected within one month prior to initiation of CAPD (predialysis) and, again, one week after initiation of uninterrupted CAPD (postdialysis). Hemoglobin A1c was measured predialysis. RESULTS: Part I: Mean hemoglobin A1c values for all groups were within the normal range; however, the mean value for CAPD patients was significantly higher than for both hemodialysis patients and healthy controls (controls, 5.21% +/- 0.6%; hemodialysis, 5.12% +/- 0.5%; CAPD, 5.78% +/- 0.6%; p < 0.01). The dialysis patients had a significantly higher mean serum AGE-peptide concentration than the control subjects (controls, 7.02 +/- 3.4 units/mL; hemodialysis, 11.9 +/- 3.6 units/mL; CAPD, 11.1 +/- 4.5 units/mL; p < 0.01). There was no difference in the mean serum AGE-peptide concentration of patients in the hemodialysis and CAPD groups. Part II: The mean hemoglobin A1c value in the diabetic predialysis patients was 9.2% +/- 1.9%. There was no difference between the predialysis and postdialysis serum AGE-peptide concentrations (predialysis, 16.9 +/- 9.6 units/mL; postdialysis, 16.0 +/- 2.9 units/mL; p = 0.78). CONCLUSIONS: Despite the increased glucose load and the higher hemoglobin A1c values, indicating poor glycemic control, nondiabetic CAPD patients did not have higher serum AGE-peptide concentrations than the nondiabetic hemodialysis patients. In diabetic patients, CAPD did not further increase the serum concentrations of AGE-peptides.

Pharmacokinetics of tazobactam M1 metabolite after administration of piperacillin/tazobactam in subjects with renal impairment.

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many beta-lactamases. The disposition of tazobactam M1 metabolite after intravenous (i.v.) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4-41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half-life and area under the plasma concentration-time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3- to 4.2-hour HD session 1 hour after the i.v. infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36-48 hours after the i.v. infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n = 2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady-state plasma concentrations of the tazobactam M1 metabolite are 14.6 micrograms/mL, 34.8 micrograms/mL, and 48.8 micrograms/mL for subjects with ClCR 20-40 mL/min (every 6 hour dosing), ClCR < 20 mL/min (every 8 hour dosing), and on CAPD (every 12 hour dosing), respectively.

Pneumoperitoneum in peritoneal dialysis patients: significance of diagnosis by CT.

OBJECTIVE: Pneumoperitoneum diagnosed by plain radiography is often a sign of gastrointestinal perforation and is unusual (0.17%) in patients on continuous ambulatory peritoneal dialysis (CAPD). These patients are prone to bacterial peritonitis, which can have overlapping clinical findings with perforated viscus. Because CT is often used to screen symptomatic CAPD patients, the reliability of pneumoperitoneum as a diagnostic sign is examined. MATERIALS AND METHODS: Records of 433 CAPD patients were examined; of these, 56 patients had had CT while on CAPD (rupture, 6; nonrupture, 50). Plain radiography and CT were examined for free air and fluid. Patients were classified according to the amount of free air detected. RESULTS: Patients with ruptured viscus had pneumoperitoneum in 5 of 6 cases by CT and 4 of 6 by plain radiography. Excluding free air, ruptured viscus could only be diagnosed in 1 of the 6 patients by CT. Patients without rupture had pneumoperitoneum in 15 of 50 cases by CT and 2 of 46 by plain radiography. No instance of pneumoperitoneum was discovered on plain radiography and not CT. CONCLUSION: Pneumoperitoneum was found by CT in 30% of nonrupture CAPD patients, therefore, CT appeared to be more sensitive than plain radiography for its detection. The presence, quantity, and distribution of free air are not helpful in separating perforations from nonperforations. The lack of pneumoperitoneum on CT was found to be a useful but not absolute diagnostic sign to exclude gastrointestinal rupture.

Renal replacement therapy in diabetic nephropathy.

The case of a patient with diabetes mellitus and renal failure is presented and discussed. This case represents the very successful course of a diabetic patient who received peritoneal dialysis for 14 years. Not all patients with end-stage renal disease (ESRD) from diabetic nephropathy are this fortunate. The success and complications of dialytic modalities are discussed by a nephrologist and nurse dialysis coordinator. Renal transplantation, the preferred treatment for most diabetic ESRD patients, is discussed by a nurse transplant coordinator. Simultaneous pancreas kidney transplantation, with its potential benefits in the future is discussed by an experienced transplant surgeon. In addition, the psychosocial issues of renal failure, dialysis, and transplantation in the diabetic patient are addressed by clinical social workers. Lastly, the very important issue of foot care and treatment, and prevention of vascular-related morbidity is discussed by a practicing podiatrist. With such a multidisciplinary approach, medical and psychosocial outcomes can be optimized for diabetic patients with renal failure.

Viscus perforation in peritoneal dialysis patients: diagnosis and outcome.

OBJECTIVE: To determine the incidence and outcome of spontaneous viscus perforation in peritoneal dialysis (PD) patients and which factors could facilitate early diagnosis. DESIGN: A retrospective chart review was done on all patients with viscus perforation and on a control group with peritonitis secondary to gram-negative organisms. SETTING: A tertiary care University Hospital Peritoneal Dialysis program. PATIENTS: All patients with surgically proven spontaneous viscus perforation from 1978 to June 1992 (n = 15). A group of control patients (n = 15) with gram-negative bacterial peritonitis was also reviewed for comparison. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Hospital days, patient survival after perforation, and return to peritoneal dialysis were the main outcomes measured. Peripheral white blood cell (WBC) count, PD fluid WBC count with differential, PD fluid cultures, radiologic information, and surgical intervention were also evaluated. Data were analyzed using the Mann-Whitney test to determine significant differences between the two groups. RESULTS: Viscus perforation occurred in 15 of the 431 patients on PD from 1978 to June 1992 (3.5%). In comparison to the control group, patients with viscus perforation had a significantly higher peripheral WBC count (p = .016), a higher mean PD fluid WBC count (p = .006), and a higher mean percentage of polymorphonuclear cells in the PD effluent (p = .038). Multiple organisms on PD fluid cultures were noted in 12 of 15 patients with perforation and in only 3 control patients. Pneumoperitoneum was seen on abdominal or chest radiograph or computerized tomographic (CT) scan in 10 of 15 patients with perforation and in only 1 of 15 patients in the control group. All patients with viscus perforation required surgery and 6 expired. Only 1 death occurred in the control group. Only 1 of the 9 patients surviving perforation was able to resume PD, in contrast to 13 of 14 surviving control patients. CONCLUSION: We conclude that viscus perforation is associated with high morbidity, mortality, and technique failure. Diagnosis may be made by repeatedly searching for intraperitoneal free air on radiograph or CT scan in patients with persistently elevated peripheral and PD fluid WBC count, and for multiple organisms on PD fluid culture.

Risk factors for peritoneal dialysis-related infections.

OBJECTIVE: To identify factors associated with peritoneal dialysis-related infections at one center. DESIGN: The study was a retrospective study of a 3-year time period with relatively stable treatment patterns. SETTING: A single center experienced academic peritoneal dialysis program. PATIENTS: Patients (N = 163) receiving peritoneal dialysis (PD) from January 1989 to December 1991 who had received treatment at home for at least one month. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Catheter-related infection and peritonitis were the main outcome measures. Variables affecting infection rates that were assessed included age, time on PD, prior end-stage renal disease (ESRD) therapy, diabetic status, catheter type, exchange device, nasal carriage of S. aureus, and prophylactic rifampin therapy. Data were analyzed with univariate as well as with a fixed-effects and a mixed-effects gamma-Poisson multiple regression model. RESULTS: Variables associated with an increased risk of new peritonitis included age under 20 years (p < 0.009; rate ratio 4.54) and nasal carriage of S. aureus (p < 0.04; rate ratio 1.75). Decreased new peritonitis risk was associated with the ULTRA Set exchange system (p < 0.008; risk ratio 0.38) and intermittent prophylactic rifampin therapy (p < 0.001; rate ratio 0.99 for each 1% time on therapy). Catheter-related infections were increased in patients who had double-cuff catheters (p < 0.003) and nasal carriage of S. aureus (p < 0.04; rate ratio 1.82). Decreased catheter-related infections were noted in older patients (p < 0.02; rate ratio 0.983/year) and increasing months of study follow-up (p < 0.03; rate ratio 0.97/month). CONCLUSION: In our program nasal carriage of S. aureus increased the risk of peritonitis and catheter-related infection. Prophylactic rifampin significantly decreased peritonitis, as did use of the ULTRA Set. Single-cuff opaque catheters had the lowest catheter infection rate. Analysis of the relationships between clinical and demographic variables and peritoneal dialysis-related infection rate can identify significant contributing or protective variables and allow peritoneal dialysis programs to develop preventive strategies to minimize the risk of infection.

Pharmacokinetics and ex vivo susceptibility of cefpodoxime proxetil in patients receiving continuous ambulatory peritoneal dialysis.

Pharmacokinetics of cefpodoxime, an extended-spectrum cephalosporin, were determined for eight noninfected patients on continuous ambulatory peritoneal dialysis (CAPD) and eight healthy volunteers. Subjects were matched for sex, age (+/- 6 years), and body weight (+/- 10 kg, except for one pair) and received a single 200-mg (cefpodoxime equivalents) oral dose of the prodrug cefpodoxime proxetil in an open-label, paired-design fashion. Dialysate (CAPD group only), plasma, and urine samples were collected and assayed for cefpodoxime by a microbiologic method. In addition, mean bactericidal titers of the effluent dialysate against selected bacterial strains often associated with CAPD-related peritonitis were determined at 6 and 24 h after the dose. There was a significant difference (P < 0.05) in all pharmacokinetic parameters between healthy and CAPD subjects, except for lag time to absorption. The mean peak plasma cefpodoxime concentration of 1.88 +/- 0.6 micrograms/ml occurred at 2.44 +/- 0.5 h for healthy volunteers, while the peak concentration of 3.25 +/- 1.4 micrograms/ml occurred at 12.0 +/- 4.2 h for patients on CAPD. The average elimination half-life in CAPD patients was approximately 12 times greater than that seen in healthy volunteers. Peritoneal dialysis had a minimal effect on cefpodoxime clearance. In healthy volunteers, 24.2% +/- 13% of the dose was recovered from the urine, in contrast to only 5.59% +/- 6.9% for CAPD patients. The mean bactericidal titers for all CAPD patients, at 6 and 24 h, were mostly less than 1:2 and did not exceed 1:4 for any of the isolates. Because of the decreased renal clearance and negligible dialysate clearance of cefpodoxime, and delayed drug absorption, the dosage interval for cefpodoxime proxetil may need to be extended in CAPD patients.

Effect of peritonitis on plasma and dialysate alpha 1-acid glycoprotein concentrations in peritoneal dialysis patients.

The effect of peritonitis on plasma and dialysate alpha 1-acid glycoprotein (AAG) concentrations was determined. Plasma and dialysate samples were obtained at the onset of infection and one month after treatment from 10 peritoneal dialysis patients with peritonitis. Plasma and dialysate samples were also obtained from 10 noninfected matched controls. Sampling was repeated after a minimum of one month. Samples were assayed for AAG by radial immunodiffusion. The mean +/- S.D. plasma AAG concentrations for patients with peritonitis and for control patients were 152.4 +/- 30.9 mg/dL and 146.6 +/- 45.0 mg/dL, respectively (p > 0.05). The dialysate AAG concentrations for nine control patients were below the limit of detection. The mean +/- S.D. dialysate concentration for the nine infected patients with detectable AAG concentrations was 15.4 +/- 9.5 mg/dL. After successful antimicrobial therapy, dialysate AAG concentrations declined. There was no obvious correlation between dialysate white blood cell count and dialysate AAG concentration during peritonitis. Peritonitis increased dialysate AAG concentrations but had no effect on plasma AAG concentrations.

Pharmacokinetics of intraperitoneal, intravenous, and subcutaneous recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis.

The pharmacokinetics of recombinant human erythropoietin (Epo) were compared after mean single 99.1 U/kg intraperitoneal (IP), intravenous (i.v.), and subcutaneous (SC) doses in eight noninfected patients on peritoneal dialysis in a randomized, three-way, cross-over fashion. Continuous ambulatory peritoneal dialysis was performed in all patients on the days of the study. The IP dose was instilled into an empty peritoneum; total dwell time was 10 hours (4 hours dry, 6 hours with 2 L of peritoneal dialysis fluid). Blood samples were collected for 96 hours following IP and SC Epo, and for 72 hours following i.v. Epo. For the IP dose, a 10-hour effluent dialysate sample was collected to determine Epo recovery. Enzyme immunoassay was used for Epo analysis. The mean apparent volume of distribution was 0.05 L/kg, equivalent to 4.5% of total body weight; the mean total body clearance was 0.08 mL/min/kg. All eight patients exhibited multiexponential decay in serum Epo concentrations following i.v. Epo. Absorption of IP Epo was significantly greater than previous reports, presumably due to its administration into a dry peritoneum. The maximum concentrations following the IP and SC doses were nearly identical, but amounted to only 5% of the maximum concentrations for the i.v. dose. Subcutaneous Epo took nearly twice as long as IP Epo to achieve peak serum concentrations (17.1 +/- 5.0 hours v 9.4 +/- 1.9 hours). Compared with the IP route, the SC dose achieved a higher area under the serum concentration time curve from time 0 to 96 hours (AUC0-96; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective open-label study evaluating the efficacy and adverse reactions of the use of Niferex-150 in ESRD patients receiving EPOGEN.

Iron supplementation is usually required in patients receiving epoetin alfa. Ferrous sulfate is commonly prescribed, however many patients experience adverse gastrointestinal effects. Adverse effects may limit the amount of iron that can be prescribed, and may lead to noncompliance. Polysaccharide-iron complex (PIC) is an iron supplement containing greater amounts of elemental iron, and may produce fewer adverse effects. This study compared the efficacy and adverse effects of PIC to a historical period of treatment with ferrous iron salts to 38 dialysis patients receiving epoetin alfa. All patients were switched to PIC, and were followed for six months. The following laboratory information was recorded: hematocrit, serum iron concentration, percent transferrin saturation, total iron-binding capacity, serum ferritin concentration. Patients were given an adverse experience questionnaire at four and six months of PIC treatment. No differences in laboratory values were noted between treatments. The amount of prescribed elemental iron increased, while iron dextran use decreased during PIC therapy. Epoetin alfa doses were unchanged. Patients reported fewer gastrointestinal adverse effects at four months, however differences at six months were less striking. PIC is as effective as ferrous sulfate in sustaining erythropoiesis in patients receiving epoetin alfa. It may produce fewer adverse effects.

Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease.

Tazobactam is an irreversible inhibitor of many beta-lactamases. In combination with piperacillin, tazobactam exhibits synergy against many beta-lactamase-producing bacteria. The pharmacokinetics of piperacillin and tazobactam were evaluated in eight normal volunteers and in 52 patients with renal dysfunction. Plasma and urine were obtained for up to 30 hours after an infusion of piperacillin and tazobactam (3 and 0.375 gm, respectively). Dialysate samples were collected from patients undergoing dialysis. Piperacillin and tazobactam concentrations were determined by high-performance liquid chromatography. Noncompartmental methods were used for pharmacokinetic analysis. Piperacillin and tazobactam total body clearance, area under the curve, and terminal elimination rate correlated with renal function. Hemodialysis removed 31% and 39% of piperacillin and tazobactam, respectively. During continuous ambulatory peritoneal dialysis, 5.5% of the piperacillin and 10.7% of the tazobactam was recovered in the dialysate over 28 hours. Peak plasma concentrations of both drugs increased minimally with decreasing creatinine clearance. Dosage alterations for creatinine clearance values less than 40 ml/min are recommended.