Hearing the silence of patients who did not receive an anticipated organ transplant: "being second in line".

Admitting more than one potential organ recipient for a single available kidney is a common practice, resulting in one patient leaving the hospital without an anticipated organ transplant. The purpose of this study was to understand the life-world of end stage renal disease (ESRD) patients and their family members who experienced the phenomenon of "being second in line" for an anticipated renal transplant. After informed consent was given, indepth, face-to-face interviews were conducted with ESRD patients or family members. Interviews with 18 ESRD patients or family members who had experienced the phenomenon of leaving the hospital without an anticipated organ transplant were included in this study. The study was conducted in an mid-South university-based urban clinic that provided a variety of treatment services for dialysis and transplant patients. The narratives were tape recorded and transcribed verbatim by the researchers or a trained medical secretary. Hermeneutical analysis was used to bring forward themes found in these narratives. These narratives allowed patients and families to describe for themselves the lived experience of this event. Themes from the narratives included (a) knowing and not knowing; (b) having high hopes for a life without dialysis; (c) wanting the transplant, but not at the expense of someone else; and (d) having no voice for your experience. The final theme presented itself in three ways: (a) silencing the experience, (b) reframing by others as a "learning experience," and (c) reframing by others as a "misunderstanding." Data from this study do not support stopping the procedure of notifying more than one potential organ recipient about an available kidney, only that this is an important and meaningful experience unique to ESRD patients and their families.

Guarded alliance relationships between hemodialysis patients and their health care providers.

To further understand the complex patient-nurse relationships surrounding end stage renal disease. Thorne and Robinson's (1987: 1988a, 1988b) framework of guarded alliance was found to be most useful. In this study, we interviewed five patients regarding their perceptions of the patient-nurse relationships they had experienced while receiving hemodialysis treatment. Our study finds that this model is very useful in understanding these ever-changing relationships. Content analysis of the transcribed interviews indicated that patients experienced all of Thorne and Robinson's relationship stages including naive trust, disenchantment, and guarded alliance. Interestingly, we also found that patients may experience the same stages of "relationship" with their dialysis machine as well.

Quality of life during and between hemodialysis treatments: role of L-carnitine supplementation.

End-stage renal disease affects every aspect of a patient's life, including perception of health and quality of life. It is likely that a hemodialysis patient's perceptions of health-related quality of life directly influence compliance with medical, nursing, and nutritional prescriptions. Because L-carnitine supplementation is known to enhance muscle strength and energy in hemodialysis patients, we hypothesized that L-carnitine supplementation would enhance a hemodialysis patient's perception of health-related quality of life. To test this hypothesis, 1 g L-carnitine or placebo was administered orally to 101 patients immediately before and after every hemodialysis treatment for 6 months. To assess health-related quality of life from the patient's perspective, the Medical Outcomes Study Short Form 36 instrument was administered before the study and at 1.5-month intervals for the duration of the study. In addition, a 10-item questionnaire designed to assess common intradialytic symptoms was administered at the end of each dialysis treatment. Other parameters analyzed included Kt/V(urea) and level of nutrition. In the 6-month group, oral L-carnitine supplementation had an early positive effect on general health (P < 0.02) and physical function (P < 0.03), but the perceived effect was not sustained throughout the 6 months of the study. In the 3-month group, L-carnitine supplementation improved vitality (P < 0.02) and general health (P < 0.01). There was no association between Kt/V(urea) and perceived health-related quality of life. Serum albumin concentration was directly correlated to how patients perceived the quality of their lives.

Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction.

We determined the pharmacokinetics of 6-methoxy-2-naphythylacetic acid (6-MNA), the active metabolite of nabumetone, in normal subjects and in subjects with impaired renal function, including subjects requiring hemodialysis. Subjects received a 1000 mg oral dose of nabumetone either as a single dose or daily for 15 days. We used a noncompartmental pharmacokinetic analysis and compared those results to a population pharmacokinetic analysis performed with nonlinear mixed-effects modeling (NONMEM). The results of the two different analyses were similar. The elimination half-life increased with decreased renal function and ranged from 22 to 44 hours. The area under the curve decreased significantly at steady state, regardless of renal function. The apparent clearance determined by NONMEM analysis increased from 0.68 L/hr after a single dose to 1.13 L/hr at steady state. The apparent volume of distribution was directly proportional to the nonalbumin protein concentration and ranged from 23 to 60 L. We conclude that the pharmacokinetics of 6-MNA in this population are complicated by possible protein binding changes. However, the increased half-life in patients with renal failure is offset by changes in the apparent volume of distribution that prevent the accumulation of 6-MNA in the serum of patients with impaired renal function. Therefore dosage adjustments may not be necessary in patients with decreased renal function.

Low-dose recombinant human erythropoietin therapy in chronic hemodialysis patients.

To test the hypothesis that low-dose recombinant human erythropoietin (r-HuEpo) would be effective and safe therapy for the anemia of end-stage renal failure, we studied 37 chronic hemodialysis patients for 3 months before and 6 months after beginning treatment with r-HuEpo, 3,000 U, administered initially intravenously (IV) three times weekly. Hematocrit increased from a mean of 25.2 vol% into the target range (mean, 32.2 vol%, a 28% increase) by 4 months. Transfusion requirements were dramatically reduced. Eight patients (22%) had exacerbated or new development of hypertension, while in trials using higher doses this occurred in 35%. Vascular access thrombosis, dialyzer clotting, and seizures were not seen more frequently during r-HuEpo therapy. Dialyzer reuse was not affected. Low-dose r-HuEpo therapy is effective in most hemodialysis patients and may be associated with less adverse effects because of the slower increase in blood viscosity. As targets are reached, downward dosage adjustments need to be smaller when using an initial low-dose regimen.

Interactions of ceftazidime and tobramycin in patients with normal and impaired renal function.

We studied the in vivo interaction of ceftazidime and tobramycin in normal volunteers and anuric patients given each drug separately or both drugs in combination. Kinetic analysis of plasma concentration data showed minor changes in the disposition of these agents when they were given concurrently. However, the resulting clearance of both tobramycin and ceftazidime was unchanged when these drugs were given concurrently. The volume of distribution of tobramycin at steady state was increased by 20% in normal volunteers when given with ceftazidime. The increase in distribution was accompanied by a slight decrease in ceftazidime elimination rate. No additional alteration in dosing over those necessary to adjust for a decrease in renal function is necessary when giving this combination.

The treatment of anemia with low-dose recombinant human erythropoietin.

Recombinant human erythropoietin is effective therapy for the anemia of chronic renal failure. Hypertension, seizures, dialysis access thromboses, and clotted dialyzers have been reported as problems associated with the use of this drug. To test the hypothesis that low-dose erythropoietin is effective and safe, we gave 37 chronic hemodialysis patients this compound (3,000 units, i.v.) three times each week for 3 months. Before and for 3 months during therapy, we measured hemoglobin, hematocrit, blood transfusions, blood pressure, access thromboses, seizures, and clotted dialyzers. After 2 months of treatment, mean hemoglobin concentration and mean hematocrit increased significantly. Five patients had no increase in either value. In 4 of these 5 nonresponders, blood loss accounted for treatment failure. Neither blood pressure nor the incidence of access thromboses, seizures, and clotted dialyzers changed during the 3 months of therapy. We conclude that recombinant human erythropoietin is effective as treatment for the anemia of chronic renal failure at much lower doses than have been reported previously. The low incidence of adverse events may be related to the low dose used.

Nizatidine disposition in subjects with normal and impaired renal function.

To test the hypothesis that renal insufficiency alters nizatidine disposition, we determined the pharmacokinetics of nizatidine and its major metabolite after a single oral dose in normal volunteers and patients with various degrees of renal dysfunction, after a single intravenous dose in normal volunteers and patients with severe renal failure and during hemodialysis. After intravenous administration the elimination half-life increased from 1.5 +/- 0.2 hours in normal volunteers to 6.9 +/- 3.3 hours in patients with renal failure. The plasma clearance decreased from 0.59 +/- 0.07 L/kg/hr in normal volunteers to 0.14 +/- 0.02 L/kg/hr in patients with renal failure. Nizatidine bioavailability was nearly 100% in normal volunteers but decreased to 75% in patients with renal failure. The volume of distribution was 1.3 +/- 0.1 L/kg in normal volunteers and was not different in patients with renal failure. Nizatidine protein binding was about 30% in normal and uremic plasma. The drug was not substantially removed by hemodialysis. Patients with creatinine clearances less than 50 ml/min/1.73 m2 should receive 150 mg nizatidine once each evening. Patients with creatinine clearances less than 20 ml/min/1.73 m2 should receive 150 mg nizatidine every other night.

Intra- and interindividual variability in sodium intake in normal subjects and in patients with renal insufficiency.

To elucidate patterns of dietary sodium ingestion in free-living subjects, we collected 26 consecutive 24-hour urine specimens in 18 subjects who had not received instructions to limit the sodium content of their diets, and who were not aware that sodium intake would be estimated from the collections. Nine subjects with plasma creatinine values less than 2 mg/dL had a mean 24-hour UNaV of 156 mEq/d, with an interindividual variability of SD +/- 38 mEq. Their intraindividual variability was 61 mEq. Nine subjects with creatinine values greater than 2 mg/dL had a mean 24-hour UNaV of 108 mEq/d (P less than 0.05). The intraindividual variability of these subjects was 39 mEq/d. Subjects with normal renal function ingested more sodium than subjects with renal insufficiency, although the variability in both groups was extensive. These data confirm and extend earlier observations and illustrate the difficulty in identifying biologic correlations in the presence of considerable intraindividual variability. They underscore the futility of estimating mean dietary sodium intake with a single or occasional 24-hour urine collection in both normal subjects and patients with renal insufficiency.

Short-term augmented calcium intake has no effect on sodium homeostasis.

To test the hypothesis that the supplementation of dietary calcium intake influences sodium homeostasis, the renin-angiotensin system, and sympathetic nervous system in a manner that might evoke a decrease in arterial blood pressure, we gave 16 participants (eight normal and eight with hypertension) placebo for 8 days, followed by 500 mg elemental calcium as the carbonate salt twice a day for 8 days. The same diet was prepared for each meal for the entire study. Sodium intake was fixed for each participant and averaged 150 mEq/day. All urine was collected every day. Blood was drawn at the end of the placebo and calcium periods for determinations of plasma renin, aldosterone, and norepinephrine values. Calcium supplementation increased urinary calcium excretion significantly in both groups. However, calcium supplementation failed to influence sodium or potassium excretion, serum electrolytes, total serum calcium, renin, aldosterone, or norepinephrine levels, or heart rate. Systolic and diastolic blood pressure were not influenced in normal subjects, but in patients with hypertension the supine systolic blood pressure decreased significantly. We conclude that blood pressure lowering effects of calcium, should they occur, are not likely the result of augmented urinary sodium excretion or of straight-forward influences on the renin-angiotensin system or sympathetic nervous system.

Nitrendipine kinetics in normal and impaired renal function.

To test the hypothesis that renal failure alters the absorption and metabolism of nitrendipine and the renal elimination of its metabolites, we gave six normal men and 16 men with various degrees of renal dysfunction a single 20 mg oral dose of nitrendipine. Plasma nitrendipine and nitrendipine pyridine analog metabolite concentrations were measured by HPLC 14 times during 48 hours after dosing. The urinary excretion of four additional metabolites was measured. Standing and supine arterial blood pressure was measured 14 times during the 48 hours after dosing. The mean nitrendipine t1/2 was 2.8 +/- 2.1 hours and that of the metabolite was 3.4 +/- 3.9 hours. No significant effect of decreased renal function on any kinetic parameter was demonstrated. Plasma nitrendipine concentrations correlated with decreased blood pressure, but metabolite concentrations did not. We conclude that renal insufficiency does not alter nitrendipine kinetics in man.

Calcium channel blockade with nitrendipine. Effects on sodium homeostasis, the renin-angiotensin system, and the sympathetic nervous system in humans.

To test the hypothesis that the antihypertensive effect of the calcium channel blocking drug nitrendipine is in part related to natriuresis, we gave 16 subjects (8 normal, 8 hypertensive) placebo for 8 days followed by nitrendipine titrated to 20 mg twice daily for 8 days. The same diet was prepared for each meal for the entire study. Sodium intake was fixed for each subject and averaged 150 mEq/day. All urine was collected every day. Blood was drawn at the end of the placebo and nitrendipine periods for renin, aldosterone, and norepinephrine values. Nitrendipine caused a significant increase (p less than 0.05) in cumulative sodium excretion of 161 mEq over 7 days in the normal subjects and 103 mEq in hypertensive subjects. Potassium excretion was unaffected. In both hypertensive and normal subjects, plasma renin and plasma norepinephrine activity increased significantly (p less than 0.05), while plasma aldosterone levels did not change. Upright systolic blood pressure decreased significantly (p less than 0.05) in both groups, whereas upright diastolic blood pressure decreased only in hypertensive subjects. We conclude that blood pressure lowering effects of this drug may be in part related to natriuresis and that calcium channel blockade may dissociate plasma renin activity from that of aldosterone.

Achieving compliance to a reduced sodium diet.

Hypertension affects at least 40 million people in the United States today. Nonpharmacological treatment of hypertension relies on modifications in the diet and lifestyle. In refractory cases, the initiation of drug treatment is necessary. Although dietary sodium restriction is widely advocated, assessment of compliance to a reduced sodium diet has been difficult. This article discusses the use of a urinary chloride titrator stick to enable patients to monitor their dietary sodium intake at home. This tool increased compliance to a low sodium diet in the test population.

The efficacy of quantitative and qualitative chloride titrators in the estimation of human salt intake.

We evaluated the utility of chloride titrator sticks for facilitating the assessment of dietary salt intake, in a systematic series of clinical trials. These inexpensive devices were applied daily to 24-h or nocturnal urine specimens, thereby avoiding the inter- and intra-subject variability in salt excretion which confounds the use of occasional 24-h urine collections. Chloride and sodium concentrations in urine were highly correlated (r greater than 0.92) in either nocturnal, diurnal, or 24-h collections. The quantitative chloride titrator estimates and measured chloride concentrations were highly correlated as well (r greater than 0.99). The qualitative chloride titrator was graded on a simple scale, and was successfully employed by outpatients attempting to limit their salt intake. Commonly used antihypertensive medications did not interfere with the determinations. Additional chloride intake, such as supplemental potassium chloride, interfered with estimates of salt ingestion, but if the daily amount of potassium chloride supplement was constant, adjustments in interpretation could be made. Renal insufficiency introduced a systematic over-estimation of salt intake by the qualitative chloride tirator, but only at high salt intakes. Relative estimates of salt intake in subjects with renal failure were still possible. We conclude that chloride titrators can facilitate the management of patients who require a prescribed salt intake.

The effect of chloride-containing potassium supplements on chloride titrator estimates of dietary sodium intake.

To examine the effect of chloride-containing potassium supplements on chloride titrator estimates of dietary sodium intake, we gave normal subjects diet containing 10, 100, or 200 mEq/d sodium in random order either as such, or supplemented with one of two potassium supplements. One regimen consisted of potassium 45 mEq/d with 12 mEq/d chloride and 33 mEq/d of citrate and gluconate; the other contained 48 mEq/d potassium and 48mEq/d chloride. Increased potassium intake with either supplemented regimen resulted in increased 24-hour potassium excretion, which was manifested in only the diurnal collections. Increased chloride intake resulted in increased urinary chloride excretion both during the day and at night. At all chloride intakes, urinary sodium and chloride excretion were highly correlated. The 48 mEq/d chloride intake generated a relationship with the same slope but with a different intercept from the other two regimens. The highest chloride intake resulted in a greater chloride titrator reading; however, the relationship was sufficiently predictable that adjustments in interpretation could be easily made. We conclude that if daily potassium chloride intake is known, chloride titrators continue to be reliable tools for estimating dietary sodium intake.

Influence of home monitoring on compliance with a reduced sodium intake diet.

To test the utility of a qualitative chloride titrator strip in facilitating compliance with a reduced sodium intake diet, we enrolled 32 patients into a randomized crossover trial comprising two study periods of four weeks each. The study periods were begun after the patients had undergone extensive instruction in the diet and the use of the strip. A high degree of correlation between the patient's and the laboratory's interpretation of the strip result was identified in 29 of the subjects. Ability to use the strip was not related to level of education. A total of 12 patients achieved compliance with the diet when using the strips. Of these, nine were able to achieve compliance without the strips. Ten patients (30%) had significantly lower sodium intake when using the strips than when they did not use them. We conclude that the use of the chloride titrator strip can be mastered by most patients and, in conjunction with dietary counseling, can facilitate compliance with a reduced sodium intake diet.

Multiple-dose ciprofloxacin kinetics in normal subjects.

To determine multiple-dose kinetics of the quinoline carboxylic acid derivative ciprofloxacin, we gave 12 normal subjects ciprofloxacin, 250 mg by mouth every 12 hr for 13 doses. Plasma concentrations were measured by HPLC after the first, seventh, and thirteenth doses. Peak and trough plasma concentrations were measured daily. Ciprofloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum serum concentrations about 1 hr after dosing. Ciprofloxacin elimination t1/2 increased from 3.71 hr after the first dose to 6.51 hr after the thirteenth dose (P less than 0.05). Apparent plasma clearance decreased from 0.823 to 0.629 l/kg/hr because of decreased nonrenal clearance. Drug cumulation did not occur throughout the experiment. We conclude that concentrations of ciprofloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be achieved in plasma and that controlled clinical trials of ciprofloxacin efficacy in selected systemic infections are warranted.

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

Interactions of moxalactam and tobramycin in normal volunteers and in patients with impaired renal function.

In studies of the in vivo and in vitro interactions of moxalactam and tobramycin, normal volunteers and anuric patients were given one of the drugs or both drugs simultaneously, and the antibiotics were incubated separately or in combination in pooled human plasma. In both normal volunteers and patients with renal failure, the rate of elimination of tobramycin increased when the drug was given in combination with moxalactam. In patients with normal renal function, the rate of elimination of moxalactam decreased when the drug was given in combination with tobramycin; in contrast, this value did not decrease when the combination was given to anuric patients. In vitro, neither drug was affected by the presence of the other. Thus, the observed changes in elimination rates apparently are not caused by a chemical interaction that can be demonstrated in vitro. However, they are of sufficient magnitude to be of potential clinical significance.