Meri K. Scott

Noni juice (Morinda citrifolia ): Hidden potential for hyperkalemia?

We report the case of a man with chronic renal insufficiency who self-medicated with an alternative medicine product known as noni juice (Morinda citrifolia). The patient presented to the clinic with hyperkalemia despite claiming adherence to a low-potassium diet. The potassium concentration in noni juice samples was determined and found to be 56.3 mEq/L, similar to that in orange juice and tomato juice. Herbal remedies and alternative medicine products may be surreptitious sources of potassium in patients with renal disease.

Influence of Hemodialysis on Gentamicin Pharmacokinetics, Removal During Hemodialysis, and Recommended Dosing

BACKGROUND AND OBJECTIVES Aminoglycoside antibiotics are commonly used in chronic kidney disease stage 5 patients. The purpose of this study was to characterize gentamicin pharmacokinetics, dialytic clearance, and removal by hemodialysis and to develop appropriate dosing strategies. Design Setting, Participants, and Measurements: Eight subjects receiving chronic, thrice-weekly hemodialysis with no measurable residual renal function received gentamicin after a hemodialysis session. Blood samples were collected serially, and serum concentrations of gentamicin were determined. RESULTS Median (range) systemic clearance, volume of distribution at steady state, and terminal elimination half-life were 3.89 ml/min (2.69-4.81 ml/min), 13.5 L (8.7-17.9 L), and 39.4 h (32.0-53.6 h), respectively. Median (range) dialytic clearance, estimated amount removed, and percent maximum rebound were 103.5 ml/min (87.2-132.7 ml/min), 39.6 mg (19.7-43.9 mg), and 38.7% (0%-71.8%), respectively. Gentamicin dialytic clearance was statistically significantly related to creatinine dialytic clearance (r(2) = 0.52, P = 0.04), although this relationship is not likely to be strong enough to serve as a surrogate for gentamicin monitoring. The pharmacokinetic model was used to simulate gentamicin serum concentrations over a one-wk period. CONCLUSIONS In clinical situations where gentamicin is used as the primary therapy in a patient receiving hemodialysis with a CAHP hemodialyzer, conventional doses after each dialysis session are not as efficient at achieving treatment targets as predialysis dosing with larger doses.

Dialyzer-dependent changes in solute and water permeability with bleach reprocessing

The effects of bleach reprocessing on the performance of high-flux dialyzers have not been comprehensively characterized. We compared the effects of automated bleach/formaldehyde reprocessing on solute and hydraulic permeability for cellulose triacetate (CT190) and polysulfone (F80B) dialyzers using an in vitro model. Dialyzers were studied after initial blood exposure (R0) and after 1 (R1), 5 (R5), 10 (R10), and 15 (R15) reuse cycles. Ultrafiltration coefficient (K(uf)), serial clearances, and/or sieving coefficients (SCs) of urea, creatinine, vancomycin, inulin, myoglobin, and albumin were determined. Urea, creatinine, and vancomycin clearances and SCs did not significantly differ from R0 to R15 with either dialyzer. Inulin clearances and SC also did not significantly change from R0 to R15 for the CT190. However, these same values for the F80B significantly increased (P < 0.05). The inulin clearance and SC values for the CT190 dialyzer were significantly higher than those for the F80B at all stages except R15. Myoglobin clearances significantly increased over 15 reuses for both dialyzers (P < 0.01). However, CT190 myoglobin clearances were significantly higher at all stages (R0 = 37.7 +/- 9.7; R15 = 52.5 +/- 8.8 mL/min) than the F80B (R0 = negligible; R15 = 41.3 +/- 16.5 mL/min; P < 0.01). Albumin pre- and postdialysis SCs significantly increased for both dialyzers (P < 0.01). K(uf) for R0 and R15 were 52.3 +/- 3.3 and 52.6 +/- 7.6 mL/h/mm Hg for CT190 (P = not significant) and 48.8 +/- 4.4 and 87.3 +/- 7.0 mL/h/mm Hg for F80B (P < 0.0001). We conclude that bleach reprocessing significantly increases larger solute and hydraulic permeability of high-flux cellulosic and polysulfone dialyzers. This effect is more pronounced for the polysulfone membrane. Until 10 reuses or greater, the removal of solutes greater than 1,500 d is significantly compromised with the polysulfone dialyzer used in this study.

Effects of Dialysis Membrane on Intradialytic Vancomycin Administration

Study Objective. To quantify the influence of hemodialyzers on vancomycin removal when the drug was infused during hemodialysis.

Levofloxacin pharmacokinetics in ESRD and removal by the cellulose acetate high performance-210 hemodialyzer

BACKGROUND No published data are available describing the pharmacokinetics of intravenous levofloxacin in patients with end-stage renal disease (ESRD). Objectives of this study are to determine the pharmacokinetics and dialytic clearance of levofloxacin and develop dosing strategies in these patients. METHODS Eight noninfected subjects receiving long-term thrice-weekly hemodialysis, with no measurable residual renal function, were administered intravenous levofloxacin, 250 mg, over 1 hour after a scheduled hemodialysis session. Blood samples were collected serially during the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum concentrations of levofloxacin were determined by high-performance liquid chromatography. Differential equations describing a 2-compartment open-infusion pharmacokinetic model were fit to each individual subjects serum concentration-time data by iterative nonlinear weighted least-squares regression analysis using Adapt II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). Ratios of maximum serum concentration (C(max)) to minimum inhibitory concentration (MIC) were calculated for common respiratory pathogens by using MIC for 90% of isolates (MIC90) data from published studies. RESULTS All subjects completed the study, and no adverse events were reported. Median systemic clearance, volume of distribution at steady state, elimination half-life, and C(max) were 37.0 mL/min (range, 12.8 to 42.7 mL/min), 103.3 L (range, 39.8 to 139.3 L), 34.4 hours (range, 28.4 to 39.3 hours), and 5.2 microg/mL (range, 4.1 to 11.3 microg/mL), respectively. Median dialytic clearance and levofloxacin reduction ratios were 84.4 mL/min (range, 61.8 to 107.6 mL/min) and 0.244 (range, 0.181 to 0.412), respectively. Median C(max)-MIC90 ratios were 10 or greater for Haemophilus influenzae, Moraxella catarrhalis, Enterobacter cloacae, and Klebsiella pneumoniae, approximately 5 for Streptococcus pneumoniae, and less than 1 for Pseudomonas aeruginosa. CONCLUSION The administration of levofloxacin to patients with ESRD as 500 mg initially, followed by 250 mg every 48 hours, will provide adequate C(max)-MIC ratios after the first and subsequent doses for most patients with respiratory tract infections caused by organisms with levofloxacin MICs of 1 microg/mL or less.

The Effects of Peracetic Acid-Hydrogen Peroxide Reprocessing on Dialyzer Solute and Water Permeability

We characterized the effects of peracetic acid‐hydrogen peroxide (PAHP) reprocessing on hemodialyzer permeability to water and solutes of various molecular weights and compared these effects within and between dialyzers. An aqueous‐based solution containing urea, creatinine, vancomycin, inulin, myoglobin, and albumin was dialyzed for 60 minutes with a hemodialyzer after undergoing 0, 1, 5, 10, and 15 reuse cycles. Solute clearance, sieving coefficient (SC), and ultrafiltration coefficient were determined. We found that PAHP reprocessing significantly decreased water and solute removal (urea, creatinine, vancomycin, inulin) by cellulose triacetate dialyzers (CT190) over 15 reuses (p<0.05) but did not affect the permeability of polysulfone dialyzers (F80A). Inulin removal was significantly lower for F80A than for CT190 (p<0.0001 and p<0.001 for clearance and SC values, respectively). Myoglobin and albumin removal by CT190 significantly decreased over 15 reuses (p<0.05), but no protein was detected in dialysate or ultrafiltrate at any reuse number for F80A. Reprocessing with PAHP alters dialyzer permeability; the effect is more pronounced for the CT190 dialyzer, but removal of solutes with molecular weight above 1500 Da is significantly lower with F80A dialyzers than with CT190. These changes in dialyzer permeability should be considered when determining optimal reuse procedures.

Determination of albumin and myoglobin in dialysate and ultrafiltrate samples by high-performance size-exclusion chromatography

A high-performance size-exclusion chromatographic method was developed, validated and implemented for simultaneous and quantitative determination of albumin and myoglobin along with inulin, vancomycin and creatinine in dialysate and ultrafiltrate samples from in vitro hemodialysis experiments. The experimental parameters including mobile phase pH, ionic strength, detection wavelength, flow-rate, injection volume were first optimized for the determination of albumin, myoglobin, inulin, vancomycin and creatinine. The peak height ratio and detection limits of the proteins were then comparatively studied at 210, 254 and 280 nm by UV and diode array detection. The method was further validated by evaluating the linearity, precision and accuracy of the proteins. The assay was finally implemented to the simultaneous and quantitative determination of the proteins in dialysate and ultrafiltrate samples.

Vancomycin assay performance in patients with acute renal failure

Objective: Fluorescence polarization immunoassays (FPIA) have been reported to overestimate vancomycin serum concentrations compared to high-performance liquid chromatography (HPLC) or enzyme multiplied immunoassay technique (EMIT) in patients with chronic renal disease. The assay manufacturer has modified the FPIA to remedy this overestimation. The purpose of this study was to compare the assay performance of two FPIAs to EMIT in acute renal failure patients receiving vancomycin and continuous venovenous hemofiltration.¶Design: Open-label trial.¶Setting: Intensive care unit in a university affiliated hospital.¶Patients and participants: 15 serum and ultrafiltrate samples were obtained from 14 critically ill patients (mean ± SD; 57 ± 12 years; 8 males/6 females).¶Measurements and results: Vancomycin concentrations were determined by a polyclonal FPIA (pFPIA) performed on the TDx system, a monoclonal FPIA (mFPIA) performed on the AxSYM system and EMIT. The coefficient of variation for all assays was < 5 %. The mean difference ± SDd between mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: –0.08 ± 1.55 and 1.24 ± 2.11 mg/l, respectively. The limits of agreement between the mFPIA vs EMIT and pFPIA vs EMIT assays in serum were: –3.18 to 3.03 and –2.99 to 5.46 mg/l, respectively.¶Conclusions: Our data demonstrate that the manufacturers changes to the pFPIA have reduced overestimation. The mFPIA appears to be an acceptable assay for measuring vancomycin serum concentrations in acute renal failure patients and does not significantly overestimate these concentrations.

Low‐Molecular Weight Protein Removal by High‐Flux Dialyzers: Basic Mechanisms and Effect of Reprocessing

William R. Clark,* Bruce A. Mueller,† Meri K. Scott,† and Steven Bander‡ *Renal Division, Baxter Healthcare Corp., McGaw Park, Illinois, and Nephrology Division, Indiana University School of Medicine, Indianapolis, Indiana, †Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafeyette, Indiana, and ‡Gambro Healthcare Patient Services, St. Louis, Missouri

Effect of cisapride on QT interval in patients with end-stage renal disease

C isapride (Propulsid, Janssen Pharmaceutica, Titusville, New Jersey) is an orally administered prokinetic agent used in the treatment of dyspepsia, diabetic gastroparesis, and gastroesophageal reflux disease. Cisapride increases gastrointestinal tract motility by enhancing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus.1 Although the drug is useful and generally well tolerated, numerous cases of QT interval prolongation, torsades de pointes, and sudden death have been reported.2–4 Cisapride-induced rhythm disturbances are most likely caused by blockade of the rapid component of the potassium rectifier current via high-affinity blockade of the human cardiac potassium channel HERG.5–7 This leads to delayed repolarization, early afterdepolarization, and potentially torsades de pointes. Clinically, cisapride-induced rhythm disturbances can be explained by pharmacokinetic and/or pharmacodynamic mechanisms. Pharmacokinetic mechanisms have been attributed to situations that result in an increase in cisapride blood concentrations secondary to inhibition of cytochrome p450 3A4 (CYP3A4) metabolism (the CYP isoenzyme primarily responsible for cisapride metabolism) by concomitant drugs3,8 (e.g., clarithromycin), disease-related alterations in drug removal (e.g., hepatic dysfunction), or higher than recommended cisapride doses.9 In fact, it has been suggested that the degree of QT interval prolongation is directly related to the cisapride serum concentration.8 Pharmacodynamic mechanisms include factors leading to additional blockade of cardiac potassium currents (concomitant drugs, diseases, electrolyte disturbances, and so forth)4,10 In May 1998, Janssen Pharmaceutica introduced labeling changes for cisapride. New contraindications to the drug were added, which included patients with renal failure. Cisapride’s manufacturer has reported that patients with renal failure were “predisposed to arrhythmias with cisapride.”11 More recently, Janssen Pharmaceutica announced that it had voluntarily stopped marketing cisapride in the United States effective July14, 2000.12 Patients who have no success with other therapies and who meet carefully defined eligibility criteria will be eligible to receive cisapride in the manufacturer’s “investigational limited-access program.”13 Two published case reports describe the occurrence of torsades de pointes in patients with end-stage renal disease (ESRD) receiving cisapride and clarithromycin2 (a well-known inhibitor of CYP3A4). It is apparent that patients with ESRD receiving drugs known to inhibit cisapride metabolism are at risk for the development of QT interval prolongation and subsequent cardiac arrhythmias. No publication to date has documented the proarrhythmic action of cisapride in patients with ESRD, in the absence of interacting drugs. The purpose of this study was to examine the degree of cisapride-induced corrected QT interval (QTc) prolongation and QT dispersion in patients with ESRD in a typical clinical setting. • • • Nine subjects with ESRD receiving dialysis treatment at the Indiana University Medical Center Outpatient Dialysis Unit were included in this study. Subjects were included in the study if their physician wanted to discontinue cisapride therapy, and they were aged .18 years of age, were receiving thrice weekly maintenance on hemodialysis, and were currently taking oral cisapride chronically. Subjects were excluded if they had serum electrolyte disturbances that may have induced QT interval changes (e.g., persistent hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia before hemodialysis sessions), or were taking medications, which, when used alone or in combination with cisapride, increase the risk of QT interval prolongation. The protocol was approved by the Indiana University-Purdue University-Indianapolis Institutional Review Board and each subject gave written informed consent before enrollment in the study. Subjects’ medical charts were reviewed and data collected for age, sex, concomitant diseases, details of cisapride therapy (indication, dose, duration of therapy), concomitant drug therapy, and serum electrolyte concentrations. Cardiac rhythm, ventricular rate, and QT intervals were determined from 12-lead electrocardiograms recorded at 50 mm/s immediately before the regularly scheduled hemodialysis session. Electrocardiograms were obtained during cisapride therapy and after cisapride had been discontinued for at least 2 weeks. The terminal elimination half-life of cisapride in a published study of patients with ESRD was 9.6 6 3.3 hours (range 5.1 to 14.1).14 Consequently, the 2-week time period allowed nearly complete elimination of cisapride from the systemic circulation. All electrocardiograms were evaluated by 2 cardiologists blinded to the treatment phase. Heart rate was determined as the average of the RR intervals obtained From the Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, Indianapolis; and the Divisions of Nephrology and Cardiology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana. Dr. Sowinski’s address is: Purdue University, Department of Pharmacy Practice, D711 Myers Building, WHS, 1001 W. 10th Street, Indianapolis, Indiana 46202–2879. E-mail: ksowinsk@iupui.edu. Manuscript received January 24, 2000; revised manuscript received and accepted May 1, 2000.