Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis.

BACKGROUND: Lanthanum carbonate is a highly effective phosphate binder with significant potential as a treatment for hyperphosphatemia in patients with end-stage renal disease (ESRD). Here, the results of a placebo-controlled, dose-ranging study are presented. METHODS: 196 patients (> or = 18 years) receiving hemodialysis for at least 6 months entered a 1- to 3-week, single-blind, placebo run-in phase. Of these, 145 patients were randomized to a double-blind phase in which they received placebo or lanthanum carbonate in daily lanthanum doses of 225, 675, 1,350 or 2,250 mg for 6 weeks. Serum levels of phosphorus, calcium and parathyroid hormone, and adverse events were monitored throughout the study. RESULTS: The intent-to-treat analysis (n = 144) showed significant dose-related reductions in serum phosphorus at lanthanum doses of 675, 1,350 and 2,250 mg. After 6 weeks of treatment, phosphorus levels were significantly lower in the lanthanum groups receiving 1,350 mg/day and 2,250 mg/day, compared with the placebo group (respective changes from randomization: -0.95 +/- 1.39 mg/dl (-0.31 +/- 0.45 mmol/l), -1.13 +/- 2.01 mg/dl (-0.36 +/- 0.65 mmol/l), 0.75 +/- 1.47 mg/dl (0.24 +/- 0.47 mmol/l), p < 0.001). Significant reductions in serum phosphorus, compared with placebo, occurred in the lanthanum 1,350 mg/day group from the second week of treatment and in the 2,250 mg/day group from the first week of treatment. Adverse events were mainly gastrointestinal (e.g. nausea and vomiting). Treatment-related adverse events occurred in 39% of patients treated with lanthanum carbonate and 44% of the placebo group. CONCLUSION: Lanthanum carbonate is an effective and well-tolerated agent for the short-term treatment of hyperphosphatemia in patients with ESRD.

Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis.

STUDY OBJECTIVE: To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy. DESIGN: Prospective, outpatient study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight patients receiving hemodialysis. INTERVENTION: We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). MEASUREMENTS AND MAIN RESULTS: Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate-ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (Cl(diffusion)) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 +/- 15% (range 13-92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (f(up)) at the time that SCs were determined was significantly lower in the PS group (0.16 +/- 0.07) than the AN69 group (0.30 +/- 0.17, p<0.01), but similar to that in the PMMA group (0.27 +/- 0.12). Despite the higher f(up), the SC of unbound ceftriaxone with the AN69 filter (0.48 +/- 0.13) was significantly lower than values for the PMMA (0.86 +/- 0.33) and PS (0.82 +/- 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p=0.006) and PS (p=0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cl(diffusion) of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters. CONCLUSION: Ceftriaxone clearance was significantly increased and membrane dependent during continuous venovenous hemofiltration and continuous venovenous hemodialysis. Thus individual ceftriaxone dosages for patients receiving continuous renal replacement therapies should incorporate extracorporeal clearance.

Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis.

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI(diffusion)) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17%+/-7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P<0.0001) were observed between CI(diffusion) of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.

A multidisciplinary renal clinic for corticosteroid-induced bone disease.

A multidisciplinary clinic to manage complicated bone disease was established due to the high prevalence of osteoporosis in corticosteroid-treated patients with a history of organ transplantation or chronic glomerulonephritis. Assessments were performed by a renal clinical pharmacist, nephrology nurse, and rheumatologist. Of 70 patients (27 men, 43 women) evaluated from December 1997-June 1999, 37% had osteoporosis (30% spine, 23% hip, 16% both sites) and 34% had a history of fracture. Analysis revealed low 1,25-hydroxyvitamin D3 levels (15 patients), hormone deficiency (16), elevated parathyroid hormone (27), and history of taking at least one other risk drug in addition to corticosteroids (58). Thirty-nine percent of patients had a documented height loss (mean 1.0 in.). Other risk factors included 32 episodes of graft rejection requiring additional corticosteroids, history of smoking (24 patients), poor physical activity (40), and low dietary calcium intake (47). Drug interventions included calcium and/or vitamin D (44 patients), calcitonin (7), alendronate (20), and hormone replacement therapy (11). Preliminary results showed an increase in bone mineral density (a surrogate marker for fracture risk) of 3-5%. An organized clinic to assess osteoporosis risks can unmask a large population of patients with documented bone loss. Appropriate interventions such as drug therapy and lifestyle changes may increase bone mineral density. A long-term benefit of therapy, although not measured in this study, may be a decreased predisposition to fractures and their sequelae.

Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials.

Clinical trials have shown the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in delaying the progression of diabetic renal disease. There is less evidence from primary clinical trials of nondiabetic renal disease. We performed an updated meta-analysis to determine the efficacy of ACE inhibitors in slowing the progression of renal disease over a broad range of functional renal impairment. We included published and unpublished randomized, placebo-controlled, parallel trials with at least 1 year of follow-up available from January 1970 to June 1999. In nine trials of subjects with diabetic nephropathy and microalbuminuria, the relative risk for developing macroalbuminuria was 0.35 (95% confidence interval [CI], 0.24 to 0.53) for individuals treated with an ACE inhibitor compared with placebo. In seven trials of subjects with overt proteinuria and renal insufficiency from a variety of causes (30% diabetes, 70% nondiabetes), the relative risk for doubling of serum creatinine concentration or developing end-stage renal disease was 0.60 (95% CI, 0.49 to 0.73) for individuals treated with an ACE inhibitor compared with placebo. Treatment of individuals with chronic renal insufficiency with ACE inhibitors delays the progression of disease compared with placebo across a spectrum of disease causes and renal dysfunction.

Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis.

The clearance of vancomycin is significantly reduced in patients with acute, as well as, chronic renal failure. Although multiple-dosage regimen adjustment techniques have been proposed for these patients, there is little quantitative data to guide the individualization of vancomycin therapy in acute renal failure patients who are receiving continuous renal replacement therapy (CRRT). To determine appropriate vancomycin dosing strategies for patients receiving continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies in five stable hemodialysis patients with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). Patients received 500 mg of vancomycin intravenously at least 12 hours before the start of the clearance study. The concentration of vancomycin in multiple plasma and dialysate/ultrafiltrate samples was determined by EMIT (Syva, Palo Alto, CA). The diffusional clearance and sieving coefficient (SC) of vancomycin were compared by a mixed-model repeated-measures analysis of variance (ANOVA) with filter and blood (Q(B)), dialysate inflow (Q(DI)), or ultrafiltration rate (Q(UF)) as the main effects and patient as a random effect. Vancomycin was moderately protein bound in these patients; free fraction ranged from 49% to 83%. The SCs of the three filters were similar and significantly correlated with the free fraction of vancomycin (P = 0.01; r2 = 0.465). Significant linear relationships were observed between the diffusional clearance of vancomycin and Q(DI) for all three filters: AN69 (slope = 0.482; r2 = 0.880); PMMA (slope = 0.853; r2 = 0.966); and PS (slope = 0.658; r2 = 0.887). The slope of this relationship for the PMMA filter was significantly greater than that of the AN69 and PS filters. The clearance of vancomycin, urea, and creatinine, however, was essentially constant at all Q(B)s for all three filters. Thus, the clearance of vancomycin was not membrane dependent during CVVH. However, during CVVHD, membrane dependence of vancomycin clearance was noted at a Q(DI) greater than 16.7 mL/min; vancomycin clearance with PMMA at a Q(DI) of 25 mL/min was 66% and 43% greater than that with the AN69 and PS filters, respectively. CVVH (62% to 262%) and CVVHD (90% to 540%) can significantly augment the clearance of vancomycin in acute renal failure patients. Dosing strategies for individualization of vancomycin therapy in patients receiving CVVH and CVVHD are proposed.

A primer on continuous renal replacement therapy for critically ill patients.

OBJECTIVES: To characterize the multiple continuous renal replacement therapy (CRRT) techniques available for the management of critically ill adults, and to review the indications for and complications of use, principles of drug removal during CRRT, drug dosage individualization guidelines, and the influence of CRRT on patient outcomes. DATA SOURCES: MEDLINE (January 1981-December 1996) was searched for appropriate publications by using terms such as hemofiltration, ultrafiltration, hemodialysis, hemodiafiltration, medications, and pharmacokinetics; selected articles were cross-referenced. STUDY SELECTION: References selected were those considered to enhance the reader's knowledge of the principles of CRRT, and to provide adequate therapies on drug disposition. DATA SYNTHESIS: CRRTs use filtration/convection and in some cases diffusion to treat hemodynamically unstable patients with fluid overload and/or acute renal failure. Recent data suggest that positive outcomes may also be attained in patients with other medical conditions such as septic shock, multiple organ dysfunction syndrome, and hepatic failure. Age, ventilator support, inotropic support, reduced urine volume, and elevated serum bilirubin concentrations have been associated with poor outcomes. Complications associated with CRRT include bleeding due to excessive anticoagulation and line disconnections, fluid and electrolyte imbalance, and filter and venous clotting. CRRT can complicate the medication regimens of patients for whom it is important to maintain drug plasma concentrations within a narrow therapeutic range. Since the physicochemical characteristics of a drug and procedure-specific factors can alter drug removal, a thorough assessment of all factors needs to be considered before dosage regimens are revised. In addition, an algorithm for drug dosing considerations based on drug and CRRT characteristics, as well as standard pharmacokinetic equations, is proposed. CONCLUSIONS: The use of CRRT has expanded to encompass the treatment of disease states other than just acute renal failure. Since there is great variability among treatment centers, it is premature to conclude that there is enhanced survival in CRRT-treated patients compared with those who received conventional hemodialysis. This primer may help clinicians understand the need to individualize these therapies and to prospectively optimize the pharmacotherapy of their patients receiving CRRT.

Clonazepam: benzodiazepine therapy for the restless legs syndrome.

Clonazepam is one of several agents used for the treatment of the restless legs syndrome of ESRD. The drug's pharmacokinetic profile demonstrates safety in patients with altered kidney function. Future studies may provide an enhanced understanding of the physiological basis of the disorder to lead to improved pharmacological therapy. Other medication alternatives such as narcotics, dopamine agonists, clonidine, and gabepentin are available for patients unable to tolerate or receive benefit from clonazepam.

Medication knowledge and compliance among patients receiving long-term dialysis.

The extent to which patients receiving longterm dialysis understood and complied with their drug therapy regimens was studied. Patients undergoing long-term hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) in a university-affiliated outpatient dialysis center were surveyed to determine their knowledge about and compliance with prescribed regimens for antihypertensives, phosphate binders, and calcitriol. They were asked to list their prescribed medications and state the medications' indications, the frequency with which they missed doses, and the actions they took after missing a dose. The patients were also asked where they obtained their medications and who their primary source of drug information was. Seventy-two patients (51 receiving hemodialysis and 21 receiving CAPD) were surveyed. Although 80% of the patients could recall the three target medications, only 39% of the hemodialysis patients and 57% of CAPD patients could recall all of their medications. Significantly more patients knew the indication for their antihypertensive medication and calcitriol than for their phosphate binder. The hemodialysis and CAPD patients reported they missed an average of 13.0 and 4.7 phosphate binder doses, 2.6 and 5.6 antihypertensive doses, and 6.7 and 7.0 calcitriol doses, respectively, per month. Despite the fact that 70% of the patients received their medications from a community pharmacy, less than 15% identified the pharmacist as their primary source of drug information. Patients receiving long-term hemodialysis or CAPD were more knowledgeable about and compliant with their antihypertensive and calcitriol regimens than their phosphate binder regimens.