Edward F. Foote

Predicting first-year relapses in children with nephrotic syndrome.

Objective. More than half of the children diagnosed with nephrotic syndrome will have relapses. These can be infrequent relapses (IRs: <2 in 6 months or <3 in a year) or frequent relaspses (FRs: >2 in 6 months or >3 in a year). Patients who relapse while on alternate day steroids or within 1 month of discontinuation of steroid therapy are considered steroid-dependent (SD; J Pediatr. 1982; 101:514–518). Patients with an IR course have a better long-term prognosis, and many of them have minimal-change disease without mesangial hypercellularity or sclerosis. The purpose of our study was to identify factors at initial presentation that could predict the relapse pattern in the first year after diagnosis, without taking into consideration the histopathology found on renal biopsy. Design. We analyzed the medical records of children who were seen by us before March 1997 and followed for at least 1 year. Variables selected in the study were age, sex, race, presence or absence of hematuria, and days to remission (defined as protein-free) at the initial presentation, because they could relate to the pattern of relapses (ie, IR, FR, and SD). Results. Of 70 patients, 14 were excluded because of insufficient data. There were 38 males (67.9%) and 18 females (32.1%), giving a male:female ratio of 1.8:1. Median age at presentation was 3.25 years (range: 1.5–13), and 76.9% were white, 8.9% black, 7.1% Hispanic, and 7.1% other. Of all the patients, 23 were IR (41.1%), 9 were FR (16.1%), and 24 were SD (42.9%). Median days to remission were 10 (range: 2–60), on Prednisone 60 mg/M2 daily. Hematuria was present initially in 26 patients (46.4%), and absent in 30 (53.6%). Age, sex, race, and hematuria, as independent variables, were not predictors of relapses in the first year. However, using a stratified analysis based on the presence or absence of hematuria, we found that if the remission occurred within the first week of therapy, the patients without hematuria were more likely to be IR. The sensitivity and specificity of this finding were 67% and 89%, respectively, with a positive predictive value of 94%. Conclusion. We conclude that of all the presenting features, the rapidity of initial response to steroid therapy combined with the presence of hematuria, could predict future relapses and should be well documented.

Clinical Presentation and Analysis of Risk Factors for Infectious Complications of Implantable Cardioverter-Defibrillator Implantations at a University Medical Center

The objective of this report is to describe the characteristics of patients who develop infections associated with implantable cardioverter-defibrillators (ICDs) implanted with sternotomy and thoracotomy approaches. A retrospective chart review identified all patients who underwent ICD implantation at a university medical center from November 1982 through February 1990. Several patient and procedural variables were compared between infected patients and noninfected patients. One hundred fifty-seven patients underwent 202 ICD generator implantations (45 generator changes), and nine of these patients developed infection (4.5% per implantation and 5.7% per patient). Of the patient variables analyzed, a significant correlation (P < .0001) was made only with a diagnosis of diabetes mellitus: 36% of diabetics versus 3.9% of nondiabetics were infected. The only patient- or procedure-specific variable that was found to correlate with the development of infection was the presence of diabetes mellitus.

Pharmacokinetics of Intraperitoneal Fluconazole during Continuous Cycling Peritoneal Dialysis

OBJECTIVE: To investigate the pharmacokinetic characteristics of intraperitoneal fluconazole in patients undergoing continuous cycling peritoneal dialysis (CCPD). DESIGN: Prospective, nonrandomized, single-dose, open-label study. PARTICIPANTS: Five noninfected volunteer CCPD patients. INTERVENTIONS: Patients received a single dose of intraperitoneal fluconazole 200 mg during their long daytime dwell. Blood samples were collected before and 1, 3, 6, 12 (end of first dwell), 24 (after overnight cycling), 48, 72, 96, and 120 hours after dosing. Used dialysate was collected throughout the study. Unless the patient was anuric, urine was collected for the first 48 hours. MAIN OUTCOME MEASURE: Fluconazole concentrations were assayed by gas–liquid chromatography. Pharmacokinetic parameters were calculated using standard noncompartmental techniques. RESULTS: The bioavailability of intraperitoneal fluconazole was 96% ± 2% over a 12-hour dwell, absorption half-life was 2.5 ± 1.2 hours, serum elimination half-life was 71.65 ± 12.76 hours, and volume of distribution was 0.66 ± 0.13 L/kg. Peritoneal clearance was 5.96 ± 0.93 mL/min and proportional to total dialysate volume. Renal clearance was proportional to renal creatinine clearance. CONCLUSIONS: Current treatment guidelines for fungal peritonitis suggest fluconazole 200 mg intraperitoneally every 24 hours. Our data suggest that this dose, administered every 48 hours, is more than sufficient to maintain serum and peritoneal concentrations above the minimum inhibitory concentration for most Candida spp. Other factors, such as residual renal function and dialysis prescription, may also need to be considered.

New Therapeutic Agents in the Management of Hypertension: Angiotensin II-Receptor Antagonists and Renin Inhibitors

OBJECTIVE: To review the chemistry, pharmacokinetics, and clinical trials of two new classes of antihypertensive drugs, angiotensin II-receptor antagonists and renin inhibitors. DATA SOURCES: Primary literature on angiotensin II-receptor antagonists and renin inhibitors was identified through a comprehensive medical literature search from 1961 through 1993. This search included journal articles, abstracts, and reports of both animal and human research published in the English language. Indexing terms included renin-angiotensin aldosterone system, renin inhibitors, angiotensin II antagonists, DuP 753, losartan, MK954, A-64662, and Ro 42–5892. STUDY SELECTIONS: Emphasis was placed on clinical and pharmacokinetic studies in humans for drugs that are currently in Phase I—III research protocols in the US. DATA EXTRACTION: All available data from human studies were reviewed. DATA SYNTHESIS: Angiotensin II-receptor antagonists and renin inhibitors may be effective antihypertensives with few adverse effects noted in the small studies completed. Their potential advantage over angiotensin-converting enzyme (ACE) inhibitors includes a possible smaller adverse effect profile. In the past, the clinical utility of angiotensin II-receptor antagonists and renin inhibitors has been limited because of poor oral bioavailability, although newer agents are more readily bioavailable. CONCLUSIONS: Angiotensin II-receptor antagonists and renin inhibitors may be the next new classes of antihypertensives marketed. However, definitive conclusions about their roles in the management of hypertension are not possible until larger clinical trials assessing their efficacy and safety and comparing them with ACE inhibitors are completed.

Calcium-Channel Blockers for Prophylaxis of Radiocontrast-Associated Nephrotoxicity

Because of both an absence of sufficient data and the concern for increased toxicity in certain patient populations, the use of CCBs to reduce radiocontrast-associated nephrotoxicity is not recommended. Additional prospective, randomized trials are needed.

Accuracy of Vancomycin Assays in Dialysis Patients

This question highlights a problem that is of some importance and appears to be unrecognized in most of the renal community. The Crystalline Degradation Product (CDPl), a biologically inactive breakdown product of vancomycin formed in vitro when solutions of vancomycin are heated, is the basis for the problem (1). While not normally detected in the serum of patients receiving vancomycin, CDP-1 has been found in the presence of renal impairment (2). It is thought that the prolonged half-life of vancomycin in patients with renal failure exposes the drug to internal body temperatures for longer periods of time, thus allowing for the degradation of vancomycin into CDP-1, which subsequently accumulates in the serum. CDP-1 is not formed in serum in vitro under routine storage conditions (i.e., room temperature, refrigerated, frozen) for up to 5 days; thus, storing samples for relatively short periods of time prior to analysis does not appear to be a problem. The clinical dilemma posed by the presence of CDP-I is that it may interfere with certain assay methods for vancomycin. Polyclonal assays such as the fluorescence polarization immunoassay (FPIA) method and the radioimmunoassay (RIA) method have been shown to overestimate vancomycin serum concentrations in the presence of CDP-1. Anne et al. studied the polyclonal RIA and FPIA methods and the monoclonal enzyme multiplied immunotechnique (EMIT) method using seven samples of negative human serum spiked with known amounts of vancomycin and CDP-1 (2). The average crossreactivity of CDP-1 with vancomycin with the FPIA, RIA, and EMIT assays was 38.6%, 67.5%, and 2.4%, respectively. In the study by Hu et al. of 50 renally impaired patients receiving vancomycin, there was an average 10% discrepancy between the EMIT and the FPIA methods (3). The report did not, however, specify the degree of renal impairment nor the duration of vancomycin therapy in these patients. To further evaluate the effect of assay methodology on vancomycin concentration, Morse et al. assayed plasma samples in nine CAPD patients receiving once weekly i.p. vancomycin (4). Serum vancomycin concentrations were measured by both FPIA and high pressure liquid chromatography (HPLC), a highly specific assay for vancomycin. The initial peak levels measured by the assays after the first dose were in close agreement, with a difference of 3.9 2 2.6 p,g/mL (not significant). However, after the second and third dose, the FPIA assay measured significantly higher peak vancomycin levels than did the HPLC assay, with mean differences of 10.9 5 8.8 and 14.1 ? 5.9 pg/mL, respectively. Peak concentrations after the second and third dose were overestimated with the FPIA assay by a mean of 52.6% +20% ( P C 0.05) and 39.6 +18.8% (P < 0.05), respectively. Trough concentrations showed a similar discrepancy between assay methods before the third dose of vancomycin. The first trough values were similar, but the second troughs were 16.1 5 6.4 (FPIA) compared with 10.2 rt 4.1 (HPLC) pg/mL (P < 0.05). This study suggests that the formation and accumulation of CDP-1 becomes clinically significant with prolonged therapy. In conclusion, the overestimation of vancomycin serum concentrations by polyclonal assay methodology such as FPIA and RIA, but not by the monoclonal EMIT assay, could lead to suboptimal dosing in renally compromised patients. The FPIA method is widely used by hospital laboratories, so it is important that clinicians be aware of the assay method employed by their institution. Because of limited data, specific guidelines to adjust for this overestimation cannot be provided. However, in renally impaired patients on prolonged therapy (more than one week), vancomycin levels should be interpreted cautiously, keeping in mind the assay method, the degree of the patients renal impairment, and the length of time the patient has been receiving the drug.

Risk of High‐Dose Erythromycin in End‐Stage Renal Disease

Is high‐dose (i.e., over 2 g daily) intravenous erythromycin contraindicated in end‐stage renal disease (ESRD) because of the risk of ototoxicity?

Nephrology: Nephrology Pharmaceutical Care Preceptorship: A Programmatic and Clinical Outcomes Assessment

Objective: The University of Pittsburgh Nephrology Pharmaceutical Care Preceptorship (NPCP) program was conceived to acquaint health system pharmacists with the pharmacotherapeutic management of dialysis patients, enhance the delivery of pharmaceutical care, and improve clinical outcomes through the development of specialized professional skills. A survey designed to determine the impact of the NPCP program was sent to all 145 participants of the program. Methods: The survey, designed to collect demographic information and data about the participants’ practice sites, professional activities prior to and after the completion of the program, and markers of disease status, was mailed to all participants in September 1997. The 96 respondents (66.2%) were involved in a wide variety of clinical practices; inpatient management of peritoneal dialysis, hemodialysis, or renal transplant patients were most commonly reported. Results: Moro than 80% of the participants believed that the educational content of the NPCP program was sufficient to allow them to establish a specialized service for the management of dialysis patients. However, two-thirds would have preferred to have more contact time (an additional 11–2 d) with the preceptorship faculty. The percentage of the pharmacists’ time devoted to the provision of pharmaceutical care for dialysis patients almost doubled, from 13.1% to 25.2% (p < 0.001). The components of pharmaceutical care performed by these pharmacists also changed as a result of their completion of the NPCP program. Time devoted to clinical services and the provision of educational programs (inservices) increased significantly, whlie the time allocated to distributive activities decreased from a mean of 32.4% to 26.4% (almost 20% from baseline). The number of pharmacists who provided some component of pharmaceutical care for ambulatory dialysis patients increased significantly, from 10 to 33, after completion of the program. In the survey given after the preceptorship, almost 70% of these 33 pharmacists self-reported that the mean hematocrit of their ambulatory dialysis patients increased; 45% reported that the epoetin dose was lower. Parenteral iron use was also reported to have increased in 78.8% of the dialysis units, and an increase in serum ferritin and transferrin saturation was observed in 54.5% and 60.6% of the units, respectively. Although far fewer pharmacists (n = 15) initialed a renal osteodystrophy management program, 73.3% of those who did so reported an increase in their patients’ compliance with phosphate binder therapy, which was reflected in a drop in serum phosphorous in 40% of the units. Conclusions: The NPCP program resulted in changes in the professional activities of the participants: fewer distributive activities and increased clinical and educational activities. These significant changes ware noted in all areas of outpatient care. Participation in the NPCP program enhanced the delivery of pharmaceutical care to dialysis patients and Improved the markers of disease status

Use of Clindamycin for Peritonitis in PD Patients.

Both clindamycin phosphate (the intravenous form) and oral clindamycin palmitate (the oral form) are without antibacterial activity until they are hydrolyzed to the hydrochloride salt. Since clindamycin is highly protein bound, the amount of antibiotic delivered to the peritoneum after systemic administration is marginal; thus systemic clindamycin is not recommended for the treatment of CAPD-related peritonitis (1). Whether CAPD related peritonitis can be effectively treated with intraperitoneal administration of clindamycin is currently uncertain due to a lack of reported data on this subject. This uncertainty is further complicated by the issue of whether clindamycin can be converted to its active form in the peritoneal cavity. Golper et al. studied the pharmacokinetics of intraperitoneal clindamycin in one infected and 10 noninfected patients (2). In the infected patient, intraperitoneal clindamycin phosphate (200 mg per 2L of dialysate exchanged every three or four hours) resulted in intraperitoneal concentrations of (activated) clindamycin of 19.5 to 47.0 mg/mL, concentrations well above the recommended therapeutic levels of 5 mg/mL. Clindamycin was discontinued shortly thereafter because the organism was resistant; thus activation during the post-exudative phase of the infection could not be documented. In the noninfected patients, the six given 50 mg/L had subtherapeutic clindamycin levels while the four given 150 mg/L had marginal concentrations (range, 2.5–6 mg/mL). In separate in vitro studies, the investigators examined the activation of clindamycin phosphate (50 mg/L) in infected and noninfected spent dialysate and found that clindamycin activity was detectable only in the infected dialysate (9.4 ± 0.7mg/mL), suggesting that something (bacteria, white blood cells, or protein) in infected dialysate can activate the antibiotic. Since there was some activation of clindamycin in vivo in noninfected patient while in vitro there was no activation, the authors speculated that some activation may be occurring at the peritoneum. These studies suggest that in the exudative stage of peritonitis, IP clindamycin phosphate is easily hydrolyzed and adequate dialysate concentrations can be achieved. However, activation in the post-exudative phase was not examined and may be significantly less. The authors suggest that clindamycin phosphate in an IP dose of 167 mg/L of dialysate will achieve adequate dialysate concentrations in the post-exudative phase based on their observation of about 3% activation in noninfected dialysate. The authors suggest the high concentrations during the exudative phase, because of enhanced activation, would act as a bolus dose early in the infection. Schwartz et al. further studied the pharmacokinetics of intraperitoneal clindamycin in nine non-infected CAPD patients (3). All patients received 300 mg/L of clindamycin in the first exchange of dialysate. Five of the patients received an additional 300 mg/L of clindamycin in the next four exchanges (group I) while the remaining four patients received 30 mg/L (group II). In group I, serum concentrations at 24 hours were 4.6 ± 1.16 mg/mL and dialysate concentrations were 7.1 ± 2.04 mg/mL. In group II, concentrations in both serum and dialysate fell below a mean of 1mg/mL by 24 hours. An in vitro study (data not presented) found that clindamycin was not activated in spent dialysate, suggesting that activation occurs at the peritoneum. This study suggests that clindamycin at doses of 300 mg/L will achieve dialysate concentrations of active clindamycin sufficient to treat peritonitis. The use of intraperitoneal clindamycin in the treatment of peritonitis is not generally recognized as a therapeutic option. A recent review indicated IP clindamycin was inactive and dismissed its use in peritonitis as inappropriate (4). The recommendations for the treatment of peritonitis from the Ad Hoc Advisory Committee on Peritonitis Management do not include the use of clindamycin (5)—probably due to a lack of clinical experience with the drug in peritonitis. In conclusion, in a patient in whom other well accepted drugs are not an option (e.g., allergy to lactams and vancomycin), intraperitoneal clindamycin may be used at a dose of 300 mg/L with every exchange. Clinicians should be aware that in the post-exudative phase, activation of clindamycin is reduced (although these dosing recommendations account for this). Besides potential pharmacokinetic limitations, another major obstacle to the widespread use of clindamycin in CAPD-related peritonitis is a high incidence of resistance by S. epidermidis, a common pathogen. Based on the available data, the pool of patients who may be considered appropriate candidates for intraperitoneal clindamycin is very small. Since there are no published data on the clinical efficacy

Availability of Quinine for Muscle Cramps in Dialysis Patients

One of my patients was told by his pharmacist that quinine will no longer be available for the treatment of leg cramps. Is this true?