Curtis A. Johnson

Parenteral iron use in the management of anemia in end-stage renal disease patients

Intravenous iron is required by most dialysis patients receiving erythropoietin (EPO) to maintain an adequate hematocrit. In the United States, there are currently two parenteral iron preparations, iron dextran and iron gluconate, approved for such use, and a third product, iron sucrose, is under development. This article reviews each of these products. Each of the iron products increases the efficacy of EPO use in anemia management. There is considerable experience in the United States and elsewhere with the use of iron dextran. Although it is clinically effective, iron dextran is also associated with significant morbidity from both dose-dependent and -independent side effects. The slow release of iron from this complex necessitates a delay in monitoring iron indices after the administration of large doses of iron dextran. Recommended doses of iron sucrose appear very safe with little risk of anaphylactic reactions. Adverse effects are uncommon and not life threatening. If approved for use in the United States, iron sucrose may be a safe and effective alternative to iron dextran. Iron dissociates from iron gluconate quite rapidly and may increase the production of ionized free iron. Iron gluconate may be a safe alternative to iron dextran for patients with severe reactions, including anaphylaxis. The risk of allergic reactions to iron gluconate is very low. The exact place in therapy for the newer iron complexes remains unclear. Currently available data suggest that iron sucrose and iron gluconate may have diminished adverse effect profiles when compared with iron dextran. Additional clinical experience will establish the role for these new iron products.

Randomized Controlled Trial of Prophylactic Rifampin for Peritoneal Dialysis-Related Infections

Staphylococcal infections are a major cause of catheter infections and peritonitis in peritoneal dialysis patients. Since catheter-related infections are associated with nasal carriage of Staphylococcus aureus in this population, we studied the effect of intermittent rifampin, an antibiotic known to decrease S aureus nasal carriage, on catheter-related infections and peritonitis. We randomly assigned 64 patients to receive either rifampin 300 mg twice daily for 5 days every 3 months or no treatment. The rifampin-treated patients had a significant delay in time to first catheter-related infection (P less than 0.015) and significantly fewer catheter-related infections overall (P less than 0.001). The catheter-related infection rate in rifampin-treated patients was .26 per patient-year versus .93 per patient-year in untreated patients. Multivariate analysis defined baseline colonization of nares or catheter exit-site and prior renal transplant as risk factors for catheter-related infections. There was no significant difference in peritonitis rates between groups, although the trend was for a delayed time to first episodes and fewer episodes in rifampin-treated patients. Adverse effects necessitated withdrawal of rifampin in four patients. We conclude that intermittent rifampin administration is effective in decreasing catheter-related infections in a peritoneal dialysis population.

Trends in Anemia Management among US Hemodialysis Patients

This study was undertaken to describe the relationship between hematocrit (Hct) and changes in the prescribed dose of erythropoietin (EPO) as well as selected patient and process care measures across annual national samples of hemodialysis patients from 1994 to 1998. This study uses the cohorts identified in the ESRD Core Indicators Project, random samples of 6181, 6241, 6364, 6634, and 7660 patients, stratified by ESRD Networks drawn for each year from 1994 to 1998. Patient demographic and clinical information was collected from October to December for each year. Surrogates of iron stores and patterns of iron and EPO administration were profiled from 1996 to 1998. Multivariable stepwise linear regression analyses were performed to adjust for potential confounding variables and to identify independent variables associated with Hct and EPO dose. Mean Hct and EPO dose increased each year from 31.1 +/- 5.2% to 34.1 +/- 3.7% and from 58.2 +/- 41.8 U/kg to 68.2 +/- 55.0 U/kg, respectively (P = 0.0001). Increasing Hct was positively associated with male gender, more years on dialysis, older age, higher urea reduction ratio and transferrin saturation, prescription of intravenous iron, and lower ferritin and EPO dose in multivariable models (all P = 0.0001). Male gender, older age, diabetes, higher Hct, and increasing weight, urea reduction ration, and transferrin saturation were associated with lower EPO doses (all P < 0.01). Conversely, intravenous EPO and iron were associated with higher prescribed EPO doses (all P = 0.0001). Although increasing Hct is associated with decreasing EPO dose at the patient level, the increase in Hct seen across years among the cohorts of hemodialysis patients in the United States has been associated with increasing doses of EPO at the population level.

The Therapeutic Use of Azathioprine in Renal Transplantation

This review discusses the pharmacokinetics, mechanism of action, clinical use, toxicities, drug interactions, and possible approaches for therapeutic monitoring of azathioprine (AZA). The drug has been used extensively in posttransplant immunosuppressive protocols. Its therapeutic use is hampered by the development of toxicities, however, especially leukopenia, which is a common criterion for dosage adjustment. Azathioprine is rapidly converted in the liver and erythrocytes to 6‐mercaptopurine (6MP), which is eventually metabolized to inactive 6‐thiouric acid (6TU). The terminal half‐lives of AZA and 6MP are 50 and 74 minutes, respectively. While renal dysfunction does not alter the disposition of AZA, hepatic insufficiency attenuates the pharmacologic activity. Immunosuppression depends on the formation of active intracellular thiopurine ribonucleotides, although AZA itself may block antigen recognition. Individualization of AZA regimens by determining tissue concentrations of thioguanine nucleotides, and plasma concentrations of AZA, 6MP, or 6TU may improve the risk:benefit ratio.

Comparative Review of the Pharmacokinetics of Vitamin D Analogues

This article reviews the pharmacokinetic characteristics of calcitriol, paricalcitol, and doxercalciferol, and provides an overview of the metabolism of vitamin D. Calcitriol and paricalcitol have similar pharmacokinetic profiles, with terminal half‐lives ranging from 5 to 10 hours in healthy subjects to 15–30 hours in patients undergoing dialysis. Both are active on intravenous administration and little of the active agent remains in the circulation after 24 hours, although they are normally given every 48–72 hours. Doxercalciferol is a prohormone, requiring hepatic metabolism to the active metabolite 1α,25‐(OH)2D2. The half‐life of 1α,25‐(OH)2D2 is about 34 hours in healthy subjects and about 45 hours in dialysis patients, resembling physiologic blood concentrations of endogenous vitamin D. More studies are warranted to determine the disposition of the vitamin D analogues, especially in selected populations such as pediatric and geriatric dialysis patients.

Subcutaneous erythropoietin results in lower dose and equivalent hematocrit levels among adult hemodialysis patients: Results from the 1998 End-Stage Renal Disease Core Indicators Project

The National Kidney Foundations Dialysis Outcome Quality Initiative (NKF-DOQI) guidelines recommend that epoetin alfa should be administered by the subcutaneous route in hemodialysis patients. We determined whether hematocrit levels in hemodialysis patients differed by route of epoetin alfa administration after controlling for demographic factors and iron status. Data were available for 7,092 of the 7,658 patients randomly chosen for inclusion in the 1997 Health Care Financing Administration Core Indicators sample. Epoetin alfa was administered to 96% of the study cohort and was administered subcutaneously in 10% of patients. After controlling for hematocrit, patient characteristics, adequacy of dialysis, iron status, serum albumin, postdialysis weight, and duration of dialysis, the epoetin alfa dose by the intravenous route was 193.6 units/kg/wk (95% confidence interval, 189.5 to 197.8 units/kg/wk) compared with 167.4 units/kg/wk (95% confidence interval, 153.9 to 180.8 units/kg/wk) for the subcutaneous route (P < 0.001). The mean hematocrit for the subcutaneous route was 32.7% +/- 3.4% and for the intravenous route was 33.0% +/- 3.2% (P < 0.05). Factors independently associated with increased hematocrit included male gender, white race, older patient age, greater number of years on dialysis, higher serum albumin concentration, higher urea reduction ratio, and percent transferrin saturation (all P < 0.001). After controlling for patient factors and weekly epoetin alfa dose, there was no association between route of epoetin alfa administration and hematocrit level (P = 0.144). Patients receiving epoetin alfa by the subcutaneous route had comparable hematocrit values using a lower epoetin alfa dose than patients receiving epoetin alfa intravenously. These data support the NKF-DOQI recommendation that epoetin alfa be administered subcutaneously in long-term hemodialysis patients.

Adsorption of Insulin to the Surface of Peritoneal Dialysis Solution Containers

Continuous ambulatory peritoneal dialysis (CAPD) is becoming widely used in diabetics with end-stage renal disease. One of the proposed advantages of this technique is the ability to administer insulin intraperitoneally. The administration of insulin by this route provides acceptable plasma glucose control with no need for subcutaneous injections. Because adsorption of insulin to glass and polyvinyl chloride (PVC) surfaces is known to occur with intravenous fluid systems, this study was conducted to measure insulin adsorption to dialysis fluid systems. The effects of time, temperature, heparin concentration, dextrose concentration, and insulin concentration in 2-L glass and PVC dialysis solution containers were studied. While all factors significantly affected adsorption to the PVC containers, the effects of heparin and dextrose were considered to be clinically unimportant. The percentage of insulin adsorbed to the PVC surface increased with increasing time and temperature and decreased with increasing insulin concentrations. Under the conditions studied, 7.1% to 9.6% of insulin added to PVC containers was lost within the first minute. Since 15 to 30 minutes is required by most CAPD patients to prepare and instill the dialysate, 10% to 20% of added insulin may be adsorbed to the PVC bad. The adsorption of insulin to the glass surfaces was rapid with 39.6% to 42.8% being lost within the first minute. All factors studied significantly affected adsorption to the glass, but the effects of time, temperature, dextrose, and heparin were considered to be of minor clinical importance.(ABSTRACT TRUNCATED AT 250 WORDS)

The Pharmacokinetics of Antibiotics Used to Treat Peritoneal Dialysis-Associated Peritonitis

Summary Antibiotics continue to be used frequently to treat CAPD-associated peritonitis. Selection of appropriate antibiotic doses and routes of administration has been based largely upon clinical experience. Early pharmacokinetic studies utilized patients being treated with IPD. The relevance of these studies to CAPD remains unknown. Little information exists on the effects of peritonitis on peritoneal drug transport. Until the effects of peritonitis during CAPD are better understood, pharmacokinetic data will be of limited value in designing specific treatment recommendations for this common complication of peritoneal dialysis.

Forging a novel provider and payer partnership in Wisconsin to compensate pharmacists for quality-driven pharmacy and medication therapy management services

OBJECTIVE To describe the Wisconsin Pharmacy Quality Collaborative (WPQC), a quality-based network of pharmacies and payers with the common goals of improving medication use and safety, reducing health care costs for payers and patients, and increasing professional recognition and compensation for pharmacist-provided services. SETTING Wisconsin between 2006 and 2009. PRACTICE DESCRIPTION Community (independent, chain, and health-system) pharmacies and private and public health care payers/purchasers with support from the McKesson Corporation. PRACTICE INNOVATION This initiative aligns incentives for pharmacies and payers through implementation of 12 quality-based pharmacy requirements as conditions of pharmacy participation in a practice-advancement pilot. Payers compensate network pharmacies that meet the quality-based requirements for two levels of pharmacy professional services (level 1, intervention-based services; level 2, comprehensive medication review and assessment services). MAIN OUTCOME MEASURES The pilot project is designed to measure the following outcomes: medication-use quality improvements, frequency and types of services provided, drug therapy problems, patient safety, cost savings, identification of factors that facilitate pharmacist participation, and patient satisfaction. RESULTS The Pharmacy Society of Wisconsin created the WPQC network, which consists of 53 pharmacies, 106 trained pharmacists, 45 student pharmacists, 6 pharmacy technicians, and 2 initial payers. A quality assurance process is followed approximately quarterly to audit the 12 network quality requirements. An evaluation of this collaboration is being conducted. CONCLUSION This program demonstrates that collaboration among payers and pharmacists is possible and can result in the development of an incentive-aligned program that stresses quality patient care, standardized services, and professional service compensation for pharmacists. This combination of a quality-based credentialing process with a professional services reimbursement schedule is unique and has the promise to enhance the ambulatory pharmacy practice model.

Vancomycin disposition during continuous ambulatory peritoneal dialysis: a pharmacokinetic analysis of peritoneal drug transport.

Expressions are presented to describe the absorption and also clearance of drugs administered into the peritoneal cavity of patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Application of the expressions to vancomycin kinetics in five male CAPD patients showed that therapeutic levels of vancomycin can readily be achieved and maintained in the systemic circulation by administering the appropriate loading and maintenance doses. The intrinsic peritoneal clearance of vancomycin reported here is higher than the apparent clearances reported previously, averaging 300 to 500 ml/min under the conditions used in this study. The low apparent clearances previously reported are useful clinically although they do not represent the true efficiency of vancomycin removal by CAPD. The degree to which apparent clearance underestimates the true intrinsic clearance is exponentially related to the dwell time of dialysate in the peritoneum. Intraperitoneal administration is a practical alternative to other routes for CAPD patients needing antibiotic or other therapy.