Patricia Schoenfeld

A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients

Current phosphate binders used in hemodialysis patients include calcium-based binders that result in frequent hypercalcemia and aluminum-based binders that result in total body aluminum accumulation over time. This investigation describes the use of a calcium- and aluminum-free phosphate-binding polymer in hemodialysis patients and compares it with a standard calcium-based phosphate binder. An open-label, randomized, crossover study was performed to evaluate the safety and effectiveness of sevelamer hydrochloride in controlling hyperphosphatemia in hemodialysis patients. After a 2-week phosphate binder washout period, stable hemodialysis patients were administered either sevelamer or calcium acetate, and the dosages were titrated upward to achieve improved phosphate control over an 8-week period. After a 2-week washout period, patients crossed over to the alternate agent for 8 weeks. Eighty-four patients from eight centers participated in the study. There was a similar decrease in serum phosphate values over the course of the study with both sevelamer (-2.0 +/- 2.3 mg/dL) and calcium acetate (-2.1 +/- 1.9 mg/dL). Twenty-two percent of patients developed a serum calcium greater than 11.0 mg/dL while receiving calcium acetate, versus 5% of patients receiving sevelamer (P < 0.01). The incidence of hypercalcemia for sevelamer was not different from the incidence of hypercalcemia during the washout period. Patients treated with sevelamer also sustained a 24% mean decrease in serum low-density lipoprotein cholesterol levels. Sevelamer was effective in controlling hyperphosphatemia without resulting in an increase in the incidence of hypercalcemia seen with calcium acetate. This agent appears quite effective in the treatment of hyperphosphatemia in hemodialysis patients, and its usage may be advantageous in the treatment of dialysis patients.

Determinants of Survival among HIV-Infected Chronic Dialysis Patients

Over 100 HIV-infected patients have initiated chronic dialysis at San Francisco General Hospital (SFGH) since 1985. This study employed retrospective analysis to identify determinants of and trends in survival among HIV-infected patients who have initiated chronic dialysis at SFGH from January 1, 1985 to November 1, 2002 (n = 115). Cohort patient survival was compared with survival after an AIDS-opportunistic illness in all HIV-infected patients in San Francisco during the study period. Higher CD4 count (hazard ratio [HR], 0.86 per 50 cells/mm(3) increase; 95% confidence interval [CI], 0.80 to 0.93) and serum albumin (HR, 0.53 per 1 g/dl increase; CI, 0.36 to 0.78) at initiation of dialysis were strongly associated with lower mortality. Survival for those initiating dialysis during the era of highly active antiretroviral therapy (HAART) was 16.1 mo versus 9.4 mo for those initiating dialysis before this time, but this difference was not statistically significant. In adjusted analysis, only a non-statistically significant trend toward improved survival during the HAART era was noted (HR, 0.59; CI, 0.34 to 1.04). By comparison, survival for all HIV-infected patients after an AIDS-opportunistic illness in San Francisco increased from 16 mo in 1994 to 81 mo in 1996. The dramatic improvement in survival that has occurred since the mid-1990s for patients with HIV appears to be greatly attenuated in the sub-group undergoing dialysis. Although this may partly reflect confounding by race, injection drug use and HCV co-infection, future attempts to improve survival among HIV-infected dialysis patients should focus on barriers to the effective use of HAART in this group.

Increasing Incidence of Human Immunodeficiency Virus-Associated Nephropathy at San Francisco General Hospital

A survey of consultations to the Division of Nephrology at San Francisco General Hospital from 1982 to 1988 found only seven cases of proven or possible renal disease matching that described for human immunodeficiency virus (HIV)-associated nephropathy (nephrotic proteinuria, rapidly progressive renal insufficiency, and focal and segmental glomerulosclerosis [FSGS] histologically). In the period from April 1, 1988 (the conclusion of the original survey) through December 31, 1990, a roughly 11-fold increase in the incidence of such cases among referrals of HIV-infected patients to the Division occurred compared with the initial experience. The patients were nearly exclusively black men, only about half of whom had intravenous drug abuse (IVDA) as an HIV risk factor. This striking increase was associated with a progressive increase in the number of black patients with acquired immunodeficiency syndrome (AIDS) in San Francisco, and in the percentage of patients with an AIDS diagnosis discharged from San Francisco General Hospital (SFGH) who were black. These data support other evidence indicating a particular vulnerability of blacks to this form of renal disease and help to reconcile data from our division with the experience reported from other centers.

Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high‐flux hemodialysis

Cidofovir is an antiviral agent used for the treatment of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. Because cidofovir is primarily eliminated by the kidneys and because its main adverse effect is nephrotoxicity, an understanding of the pharmacokinetic disposition of cidofovir in patients with renal insufficiency is necessary.

Effects of a Magnesium-Free Dialysate on Magnesium Metabolism During Continuous Ambulatory Peritoneal Dialysis

While the use of magnesium-containing compounds is usually contraindicated in dialysis patients, the risk of toxicity from hypermagnesemia can be reduced by lowering the magnesium concentration in dialysate. We examined the effects of a magnesium-free dialysate on both serum magnesium level and the peritoneal removal rate of magnesium over 12 weeks in 25 stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD). After 2 weeks, the serum magnesium level decreased from 2.2 to 1.9 mg/dL (0.9 to 0.8 mmol/L) (P less than .02) and the peritoneal removal rate increased from 66 to 83 mg/d (2.8 to 3.5 mmol/d) (P less than .05), with both values remaining stable thereafter. There was a strong association between these parameters (r = -0.62, P less than .05), suggesting that the serum magnesium level decreased as a result of the initial increased peritoneal removal rate. For an additional 4-week period, a subgroup of nine patients received magnesium-containing, phosphate binding agents instead of those containing only aluminum. During this phase, serum inorganic phosphorus was well controlled. The serum magnesium level increased only from 1.8 to 2.5 mg/dL (0.7 to 1.0 mmol/L) (P less than .05), due in great part to the concomitant 41% rise in peritoneal magnesium removal from 91 to 128 mg/d (3.8 to 5.3 mmol/d) (P less than .05). No toxicity was noted during the entire 16-week study period, nor did serum calcium change. Thus, serum magnesium levels remained within an acceptable range as magnesium-containing phosphate binders were given through the use of magnesium-free peritoneal dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations.

BACKGROUND Foscarnet is an antiviral agent commonly used for managing patients with cytomegalovirus infection. Despite its clinical usefulness, foscarnet is associated with substantial adverse effects including nephrotoxicity. Moreover, foscarnet is primarily eliminated unchanged through the kidneys, thus requiring aggressive dose adjustment during kidney failure. To develop specific dosage guidelines, information on the disposition of this compound in patients with varying degrees of renal function and those requiring dialysis is essential. DESIGN Twenty-six subjects were enrolled in this study and divided into five groups depending on their degree of renal dysfunction. Group 1 included subjects with normal renal function; group 5 included subjects requiring maintenance hemodialysis. Nondialysis study subjects received a single 60-mg/kg intravenous dose of foscarnet whereas hemodialysis subjects received two intravenous doses, separated by 1 week, to compare the effects of conventional and high-flux dialysis methods. RESULTS Mean plasma clearance in control subjects averaged 2.1+/-0.7 ml/minute/kg and declined proportionally with changing renal function as indicated by the regression equation: Clp (ml/minute/kg) = 1.48 [CrCl (ml/minute/kg)]-0.08 (r2 = 0.82). Mean half-life averaged 1.9+/-0.1 hours in normal subjects and increased to a mean of 25+/-19 hours in study subjects with severe impairment not on dialysis. Foscarnet dialysis clearance (based on dialysate recovery) averaged 183 ml/minute with conventional dialysis methods and 253 ml/minute during high-flux procedures, which resulted in removal of 37% and 38% of a dose for the two methods, respectively. CONCLUSIONS These data indicate that substantial dosage adjustments must be made in renal failure patients. Therefore, a patient-specific dosage nomogram has been developed.

Patients with HIV infection and end-stage renal disease

There has been a steady increase in the number of dialysis patients with human immunodeficiency viral (HIV) infection. HIV-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease in this patient population. Although the major potential category of risk of HIV transmission is from the dialysis patient to staff, there are no data to indicate that this has occurred. Dialysis of patients with HIV infection is challenging and requires effective care to prolong survival.

Teicoplanin pharmacokinetics and bioavailability during peritoneal dialysis

The pharmacokinetics of teicoplanin in serum and dialysate were examined in a crossover study after intravenous and intraperitoneal administration of a 3 mg/kg dose to five anuric patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD). Blood and dialysate samples were obtained for 30 and 15 days, respectively, and were assayed microbiologically. The principal pharmacokinetic parameters after intravenous administration were as follows: total body clearance, 2.76 ± 1.08 ml/min; elimination half‐life, 377 ± 109 hours; volume of distribution at steady state, 1.04 ± 0.18 L/kg. Only 9% ± 6% of the intravenous dose was recovered in the dialysate and the net peritoneal clearance was 0.25 ± 0.21 ml/min. Bioavailability values, which were assessed by use of three methods after intraperitoneal administration and while dialysate was retained in the peritoneal cavity for 5 hours (dwell time), were 0.77 ± 0.21, 0.78 ± 0.05, and 0.76 ± 0.08. Changes in bioavailability with dwell time were also examined. A dosing guide, which accounts for changes in bioavailability with dwell time, is presented.

Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure

The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end‐stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 ± 41.5 to 65.4 ± 42.0 ml/min, and its elimination half‐life (t½) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady‐state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t½ of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t½ to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t½ prolonged in ESRD from 194.6 ± 31.9 to 76.4 ± 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.