Risk Behavior and Reciprocity of Organ Donation Attitudes in Young Men.

BACKGROUND: Lack of donor organs remains a major obstacle in organ transplantation. Our aim was to evaluate (1) the association between engaging in high-risk recreational activities and attitudes toward organ donation and (2) the degree of reciprocity between organ acceptance and donation willingness in young men. METHODS: A 17-item, close-ended survey was offered to male conscripts ages 18 to 26 years in all Swiss military conscription centers. Predictors of organ donation attitudes were assessed in bivariate analyses and multiple logistic regression. Reciprocity of the intentions to accept and to donate organs was assessed by means of donor card status. RESULTS: In 1559 responses analyzed, neither motorcycling nor practicing extreme sports reached significant association with donor card holder status. Family communication about organ donation, student, or academic profession and living in a Latin linguistic region were predictors of positive organ donation attitudes, whereas residence in a German-speaking region and practicing any religion predicted reluctance. Significantly more respondents were willing to accept than to donate organs, especially among those without family communication concerning organ donation. CONCLUSIONS: For the first time, it was shown that high-risk recreational activities do not influence organ donation attitudes. Second, a considerable discrepancy in organ donation reciprocity was identified. We propose that increasing this reciprocity could eventually increase organ donation rates.

Hemodynamic modeling of the intrarenal circulation.

Three dimensional, time dependent numerical simulations of healthy and pathological conditions in a model kidney were performed. Blood flow in a kidney is not commonly investigated by computational approach, in contrast for example, to the flow in a heart. The flow in a kidney is characterized by relatively small Reynolds number (100 < Re < 0.01-laminar regime). The presented results give insight into the structure of such flow, which is hard to measure in vivo. The simulations have suggested that venous thrombosis is more likely than arterial thrombosis-higher shear rate observed. The obtained maximum velocity, as a result of the simulations, agrees with the observed in vivo measurements. The time dependent simulations show separation regimes present in the vicinity of the maximum pressure value. The pathological constriction introduced to the arterial geometry leads to the changes in separation structures. The constriction of a single vessel affects flow in the whole kidney. Pathology results in different flow rate values in healthy and affected branches, as well as, different pulsate cycle characteristic for the whole system.

Forced fluid removal in critically ill patients with acute kidney injury.

PURPOSE: The aim was to test the feasibility of protocol-driven fluid removal with continuous renal replacement therapy (CRRT) in patients in whom standard fluid balance prescription did not result in substantial negative fluid balances. MATERIALS AND METHODS: In 10 mechanically ventilated patients with sepsis or signs of inflammation and acute kidney injury [age 65 (48-78 years; median, range), simplified acute physiology score II 66 (39-116)], fluid removal was guided by mean arterial pressure (MAP), cardiac index (CI), mixed venous oxygen saturation (SvO(2)), lactate/base excess, peripheral circulation, and filling pressures, and adjusted hourly with the goal to maximize volume removal for up to 3 days. RESULTS: Fluid removal rates during the 3 days before and during the study period [66 (36-72) h] were 11 (-30 to +36) ml/kg/day and -59 (-85 to -31) ml/kg/day, respectively (P = 0.002). In 12% of a total of 594 fluid removal rate evaluations, fluid removal had to be decreased or stopped. Most frequent reasons leading to decreasing fluid removal were (n, % of all instances, median lowest value from all patients): SvO(2) (44, 28%, 59%), MAP (36, 23%, 57 mmHg), CI (26, 17%, 2.4 l/min/m(2)), low peripheral temperature (22, 14%, 'cold'). Overall, systemic hemodynamics remained stable throughout the study period. CONCLUSIONS: In these patients, protocolized fluid removal with CRRT was associated with large negative fluid balances.

Velocity recovery cycles of human muscle action potentials in chronic renal failure.

OBJECTIVE: To test the hypothesis that muscle fibers are depolarized in patients with chronic renal failure, by measuring velocity recovery cycles of muscle action potentials as indicators of muscle membrane potential. METHODS: Velocity recovery cycles were recorded from brachioradialis muscle by direct muscle stimulation in 13 patients, before, immediately after, and 1h after haemodialysis, and compared with those from 10 age-matched controls. RESULTS: In the patients, supernormality was reduced by 47%, and relative refractory period increased by 60.5% compared with controls (both P<0.001). Dialysis normalized the supernormality, but an hour later it was again reduced. These changes in supernormality were strongly correlated with the changes in serum potassium levels (P<0.0001). A late component of supernormality, attributed to potassium accumulation in the t-tubule system, was also reduced in the patients but remained abnormally low after dialysis. CONCLUSIONS: Muscle membranes in the patients were chronically depolarized by hyperkalemia. Whereas dialysis transiently normalized muscle membrane potential, it was not adequate to normalize t-tubule function. SIGNIFICANCE: Chronic muscle membrane depolarization by hyperkalemia may account for some of the functional deficits in uremic myopathy. Consistent normalization of membrane potential by avoiding hyperkalemia may therefore reduce symptoms of 'uremic myopathy'.

The prevalence of penicillin-non-susceptible Streptococcus pneumoniae among children aged < 5 years correlates with the biannual epidemic activity of respiratory syncytial virus.

This study investigated whether the epidemiology of penicillin-non-susceptible pneumococci (PNSP) colonising small children correlated with the biannual epidemic activity of respiratory syncytial virus (RSV). Colonisation rates and the prevalence of PNSP among paediatric outpatients aged < 5 years was analysed between January 1998 and September 2003 using an established national surveillance network. Resistance trends were investigated using time-series analysis to assess the correlation with the biannual pattern of RSV infections and national sales of oral paediatric formulations of antibiotics and antibiotic prescriptions to children aged < 5 years for acute respiratory tract infections. PNSP rates exhibited a biannual cycle in phase with the biannual seasonal RSV epidemics (p < 0.05). Resistance rates were higher during the winter seasons of 1998-1999 (20.1%), 2000-2001 (16.0%) and 2002-2003 (19.1%), compared with the winter seasons of 1997-1998 (8.2%), 1999-2000 (11.6%) and 2001-2002 (9.5%). Antibiotic sales and prescriptions showed regular peaks during each winter, with no significant correlation with the biannual pattern of RSV activity and seasonal trends of PNSP. RSV is an important determinant of the spread of PNSP and must be considered in strategies aimed at antimicrobial resistance control.

A new Bayesian method to forecast and fine tune individual hemodialysis dose.

BACKGROUND: The most commonly used formulas for hemodialysis dose are based on single-pool urea kinetics; i.e., they consider the body as a single compartment and use an ad hoc adjustment for postdialysis urea rebound. We present a new urea kinetic modeling approach, individualized Bayesian urea kinetic modeling (IBKM), which incorporates prior knowledge. This method uses measurements made during previous treatments to forecast a patient's postdialysis urea rebound and clearance and provides a choice of possible dialysis parameters to achieve a desired clearance goal. METHODS: We used data from 18 patients (a total of 38 hemodialysis sessions) to build the model. All patients had been on thrice-weekly hemodialysis for at least 1 year before enrollment, and their dialysis prescription remained unchanged during the study period. Recorded variables included blood urea nitrogen (BUN) measurements and dialysis prescription parameters (dialyzer size, KoA, treatment time, blood and dialysis flow). The population distribution of urea kinetic parameters-derived from the 18 patients' data-and individual urea kinetic data (i.e., pre- and postdialysis BUN) are used in the IBKM method to make individual predictions. RESULTS: Estimates (mean+/-SE) of population urea kinetic parameters are generation rate 0.17+/-0.01 mmol/min, clearance between extracellular and intracellular compartments 646+/-60 mL/min, and total volume of distribution 31.5+/-1.5 L, of which the extracellular volume is 36+/-4%. The effective dialysis clearance is estimated to be 9.0+/-1.7%, less than the expected dialyzer clearance. IBKM predictions of postdialysis equilibrated BUN concentrations are accurate: a root mean squared error of 3.4% of the "postrebound" BUN concentration at 30 min, a value in the range of urea measurement error itself. CONCLUSIONS: IBKM can estimate not only the urea kinetics of an actual hemodialysis, but it can also predict a patient's target hemodialysis dose for any desired, flexible hemodialysis treatment. The method should prove useful for bedside monitoring, forecasting, and fine tuning of hemodialysis dose.

Epithelial sodium channel (ENaC) subunit mRNA and protein expression in rats with puromycin aminonucleoside-induced nephrotic syndrome.

In experimental nephrotic syndrome, urinary sodium excretion is decreased during the early phase of the disease. The molecular mechanism(s) leading to salt retention has not been completely elucidated. The rate-limiting constituent of collecting duct sodium transport is the epithelial sodium channel (ENaC). We examined the abundance of ENaC subunit mRNAs and proteins in puromycin aminonucleoside (PAN)-induced nephrotic syndrome. The time courses of urinary sodium excretion, plasma aldosterone concentration and proteinuria were studied in male Sprague-Dawley rats treated with a single dose of either PAN or vehicle. The relative amounts of alphaENaC, betaENaC and gammaENaC mRNAs were determined in kidneys from these rats by real-time quantitative TaqMan PCR, and the amounts of proteins by Western blot. The kinetics of urinary sodium excretion and the appearance of proteinuria were comparable with those reported previously. Sodium retention occurred on days 2, 3 and 6 after PAN injection. A significant up-regulation of alphaENaC and betaENaC mRNA abundance on days 1 and 2 preceded sodium retention on days 2 and 3. Conversely, down-regulation of alphaENaC, betaENaC and gammaENaC mRNA expression on day 3 occurred in the presence of high aldosterone concentrations, and was followed by a return of sodium excretion to control values. The amounts of alphaENaC, betaENaC and gammaENaC proteins were not increased during PAN-induced sodium retention. In conclusion, ENaC mRNA expression, especially alphaENaC, is increased in the very early phase of the experimental model of PAN-induced nephrotic syndrome in rats, but appears to escape from the regulation by aldosterone after day 3.

DNR orders at a tertiary care hospital--are they appropriate?

QUESTIONS UNDER STUDY: There are no established recommendations in Switzerland on when, how and for what patients DNR orders should be written. Moreover, little is known about current attitudes, patients' preferences, patients' involvement in decision-making and the adequacy of such decisions. The study was conducted in a Swiss tertiary care hospital to investigate the epidemiology, manner of application and appropriateness of DNR orders. METHODS: We performed retrospective chart review of all patients admitted to the department of general internal medicine of a Swiss tertiary care university hospital during four randomly selected months of the year 1998 (group 1) as well as of all patients who died in the department during 1998 (group 2). We assessed the frequency of DNR orders on admission and before death, their association with age, sex, diagnostic category, comorbidity and physical/social dependence, and the frequency of patient and/or family involvement in decision-making. RESULTS: On admission, a DNR order was written for 15% of all hospitalised patients and 54% of the patients dying during the observation period; 93% of patients ultimately dying were the subject of DNR orders before death. There was a significant association between DNR orders and patients' age (p <0.001), physical and/or social dependence (p <0.001) and the admission diagnoses malignancy (p <0.001) or acute stroke (p <0.005). Cardiovascular disease was in inverse ratio to DNR orders (p <0.001). Only 6% of either patients or families were reportedly involved in decisions in the overall group, whereas this was the case in 58% of patients who died in hospital. CONCLUSIONS: The frequency of DNR orders on admission was rather high. Referring to pre-arrest morbidity, DNR orders were often inappropriate on hospital admission but usually became so during hospital stay. After exclusion of confounding factors, age was the main independent factor for DNR orders. Patient and/or surrogate involvement in decision-making for DNR orders was low, thereby raising important ethical issues such as patient autonomy. An urgent national discussion on the topic is needed.

[Renal biopsy: standard procedure of modern nephrology]. / Die Nierenbiopsie--ein unverzichtbares Routine-Verfahren der modernen Nephrologie.

For more than 50 years, renal biopsy has been an important diagnostic procedure in modern nephrology. Increasing perfection of the biopsy technique has made the procedure very safe, with rare complications and few contraindications. Improved histological diagnostics and broader therapeutic possibilities have significantly expanded the indications. The most important indications are acute renal failure, proteinuria > 1 g/d (or 3 g/d) and nephritic urinary sediment. Complications with renal grafts provide additional indications for a renal biopsy. In addition, diabetes and monosymptomatic urinfindings (isolated haematuria) as well as pregnancy induced nephropathy are indications for a renal biopsy. The procedure is performed ambulatory or during a short hospital stay and the patient can usually be discharged after a monitoring period of eight hours.

Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful.

PURPOSE: Acute renal failure induced by contrast media is an important cause of hospital-acquired renal insufficiency. Preexisting renal failure and the dose of contrast media are known risk factors for the development of radiocontrast nephropathy. We performed a randomized trial to test whether radiocontrast nephropathy can be avoided by prophylactic hemodialysis immediately after the administration of contrast media in patients with impaired renal function. SUBJECTS AND METHODS: Renal function and other parameters, hemodialysis requirement, and relevant clinical events were recorded before and during the 6 days after administration of contrast media in 113 patients with a baseline serum creatinine level >200 microm/L (>2.3 mg/dL). Patients were randomly assigned to either hemodialysis (n = 55) or nonhemodialysis (n = 58) treatment after parenteral low-osmolality contrast media. RESULTS: The characteristics of the patients in the two groups were similar. Compared with baseline levels, the mean [+/- SD] serum creatinine level decreased at day 1 (277 +/- 95 microm/L), peaked at day 4 (353 +/- 126 microm/L), and returned to baseline at day 6 (327 +/- 119 microm/L, P <0.05 by analysis of variance) after administration of contrast media in the hemodialysis group, whereas in the nonhemodialysis group, no significant changes in mean serum creatinine level were observed. Eleven patients required 1 or more hemodialyses (8 in the hemodialysis group and 3 in the nonhemodialysis group, P = 0.12), 6 of whom (4 vs. 2, P = 0.44) required 3 or more hemodialyses. Clinically relevant events included pulmonary edema (1 vs. 4 patients, P = 0.36), myocardial infarction (2 vs. 2), stroke (2 vs. 0, P = 0.24), and death (1 vs. 1). CONCLUSIONS: The strategy of performing hemodialysis immediately after the administration of low-osmolality contrast media in all patients with a reduced renal function did not diminish the rate of complications, including radiocontrast nephropathy.

Body mass index: a measure for longevity.

Body mass index has important predictive value for mortality and morbidity both in normal subjects and in those suffering from particular pathologies. However, body mass index was introduced as a measure of body fat, which might not be expected to have such wide implications for various pathological conditions. We argue here that body mass index may actually be a measure for longevity. Our arguments are based on a well-established allometric scaling law for physiological time. The time between heart beats, the time between respirations, and longevity all scale as body weight to the 1/4 power in mammalian species ranging from shrews to blue whales. We find that body mass index also scales with body weight to the 1/4 power in humans from birth to one year of age, and again from approximately 5 to 17 years of age. On the assumption that in these two growth phases humans scale as do species, we postulate that body mass index is a measure of longevity.

[Which hypertensive patient requires diuretic therapy?]. / Welcher Hypertoniker braucht Diuretika?

Over the last decade the role of diuretics as first-line agents for the treatment of hypertension has diminished substantially. The present review encourages the reader to reconsider the current trend for a decline in the use of these inexpensive antihypertensive drugs whose efficacy is well documented. Diuretics have been used in 16 placebo controlled studies with over 13,000 patients as first-line drugs to lower blood pressure. These drugs were shown to reduce total mortality by 11%, cerebrovascular events by 34% and coronary morbidity by 29%. The magnitude of blood pressure reduction with low-dose thiazide diuretics is comparable to that of a therapy with high-dose thiazides, without the serious metabolic side effects observed with the higher dosage. In combination with other antihypertensive agents, diuretics counteract the compensatory regulatory responses, such as volume expansion and edema formation. Moreover, it has been shown that a combination with low-dose thiazides may not only further decrease blood pressure but also reduce cerebrovascular and coronary mortality. Advantages of diuretics in the treatment of hypertension can be appreciated in special clinical conditions, for instance in patients with edema, heart failure, renal failure, nephrotic syndrome and portal hypertension. Low-dose diuretics still have a place as first-line drugs for the treatment of mild, uncomplicated essential hypertension. Moreover, as opposed to other blood pressure lowering agents, there is sufficient scientific evidence for the primary preventive effect of low-dose thiazide.

Novel dialysis cannulas: are they worth the higher price tag?

Accessory hemodialysis equipment, including dialysis cannulas, usually lack controlled and independent testing before being introduced onto the market. The aim of this study is a prospective comparison of a newly designed curved-tip dialysis cannula with a standard dialysis cannula of the same size from the same manufacturer. Fifteen chronic dialysis patients were enrolled onto a prospective 4-month crossover study. All patients had arteriovenous fistulas, except for two patients with polytetrafluoroethylene grafts. The routinely used standard cannulas were replaced by either a curved-tip 15G cannula or a new standard 15G cannula from the same manufacturer. The two cannulas were compared with respect to puncture-related pain and/or problems and bleeding complications, as well as blood-flow dynamics. Venous and arterial access pressures were recorded at blood-flow rates of 100 to 400 mL/min. Linear regression analyses of arterial and venous pressure profiles showed the same regression lines for the standard and curved-tip cannulas. Plasma haptoglobulin levels and occlusion times necessary to stop bleeding after removal of the cannulas did not differ between the two cannulas. Both patients and nurses independently reported equal puncture-related pain and/or problems for both cannulas on visual analogue scales. No correlation was found between puncture problems reported by nurses and puncture pain reported by patients. The curved-tip cannula does not offer an advantage compared with the less expensive standard cannula. Controlled testing of advertised advantages by manufacturers of accessory equipment should be a prerequisite before introduction into routine clinical treatment.

Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis.

AIMS: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD). METHODS: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days. RESULTS: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session. CONCLUSIONS: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.

Urea kinetics and dialysis treatment time predict vancomycin elimination during high-flux hemodialysis.

BACKGROUND: Hemodialysis sessions with high-flux filters ask for a reconsideration of the kinetics of xenobiotics. The aim of this study was to analyze whether individual high-flux hemodialysis treatment parameters are of predictive value for dosing guidelines, with use of vancomycin as a model compound. METHODS: Twenty-six patients receiving high-flux hemodialysis were studied prospectively. After an intravenous infusion of 1000 mg or 500 mg vancomycin, respectively, six to eight blood samples were collected within a period of 5 to 9 days, including one hemodialysis session. Serum vancomycin concentrations were measured by HPLC. Nonlinear mixed-effects modeling (NONMEM) was used to fit a two-compartment population pharmacokinetic model to the data of 20 patients; the data of the remaining six patients (group II) were used for a prospective evaluation of the model. RESULTS: A linear relationship was found between vancomycin filter clearance (CLDV) and urea filter clearance (CLDBUN), derived from Kt/V (the product of urea clearance [K] and dialysis treatment time [t], standardized for the urea volume of distribution [V]). Mean (coefficient of variation) steady-state volume of distribution was 1.05 L/kg (22%), CLDV was 0.336.CLDBUN (13%), and residual interdialytic clearance was 2.25 ml/min (90%) in patients with creatinine clearance values (CLCR) below 2 ml/min and 2.25 ml/min + 0.59.CLCR (32%) in patients with CLCR values above 2 ml/min. The model predicted predialysis vancomycin concentrations before the first and the second postinfusion dialysis session in the six patients of group II, with a deviation of 1.8 +/- 1.0 mg/L and 0.8 +/- 0.5 mg/L, respectively. CONCLUSION: The described population pharmacokinetic model allows individualization of vancomycin dosing intervals in patients receiving hemodialysis, based on patient characteristics and urea kinetic modeling.

Clinical outcome relative to the dose of dialysis is not what you think: the fallacy of the mean.

Several recent retrospective studies of mortality relative to the dose of dialysis have been widely interpreted to indicate that adequate thrice-weekly hemodialysis requires a single pool Kt/V (spKt/V) of at least 1.4 to 1.6 and higher. In these studies, mortality rate has been correlated to the mean delivered spKt/V, (spKt/Vd)m, with coefficient of variation (CV) on the means ranging up to 45%. To evaluate these reported relationships, two large databases were analyzed using population constants to transform urea reduction ratio and spKt/Vd to equilibrated Kt/Vd (eKt/Vd), which expresses dose corrected for treatment time. The eKt/V dose (D) values were correlated to the reported relative risks (RR) of mortality to derive a RR/D function. The RR/D function, derived from these data with stepwise linear regression analysis, is nonlinear, with a steep linear increase in RR for eKt/Vd less than 1.05 and constant RR for eKt/Vd > or = 1.05. This RR/D function is mathematically expressed as RR = 1.96 - 1.03(eKt/Vd) (equation 1) when 0.50 < or = eKt/Vd < or = 1.05, and RR = 0.88 (equation 2) when eKt/V > or = 1.05. We show that regression of RR on (eKt/Vd)m with large CV results in overestimation of RR relative to eKt/Vd for individual patients because of extrapolation of the linear relationship beyond the threshold where the slope becomes zero (see equation 2 above). It is concluded that (1) current clinical data indicate that adequate dialysis is provided with eKt/Vd of 1.0 to 1.1 on a thrice-weekly schedule, (2) it is essential to assure that all patients achieve this level of therapy, which is best accomplished using urea kinetic modeling for both prescription and measurement of delivered eKt/Vd, and (3) the current HEMO study is well designed to determine whether higher levels of eKt/Vd will further improve clinical outcome.

Acute cyclosporine-induced nephrotoxicity in renal transplant recipients: the role of the transplanted kidney.

Cyclosporine A causes an acute reduction in GFR. The interindividual variable reduction in GFR is most likely the result of arteriolar vasoconstriction. Vasoconstriction is attributable either to a local effect of cyclosporine on renal blood vessels (intrinsic mechanism) or to a systemic effect of cyclosporine on circulating and/or neuronal factors (extrinsic mechanism). The aim of the investigation presented here was to establish whether intrinsic or extrinsic mechanisms account for the interindividual differences in the susceptibility to acute cyclosporine-induced nephrotoxicity. For that purpose, this study took advantage of the clinical transplant situation in which two (intrinsically identical) kidneys from a cadaveric donor are transplanted into two (extrinsically) different subjects. The preexisting regular daily cyclosporine doses were raised by 25% for 2 wk and by 50% for another 2 wk in 16 patients with stable renal graft function, representing eight pairs of patients, each of whom had received kidneys from the same donor. In these patients, a mean (+/- SD) maximum cyclosporine-induced increase in serum creatinine concentration of 13 +/- 11% (P < 0.001) and in serum BUN of 27 +/- 33% (P < 0.01), together with a decline in the fractional uric acid excretion of 51 +/- 89% (P < 0.02) were observed. The percentage change in serum creatinine concentrations after increased dosing of cyclosporine paralleled within the subjects receiving their kidneys from the same donor, i.e., when one recipient experienced a large percentage of change after increases of cyclosporine dosing, the corresponding recipient of a kidney from the same donor had a change of the same magnitude. Seven of eight pairs showed a consistent response with respect to a clinically significant increase in serum creatinine concentration of > 15%, with a consistent response purely by chance being < 5%. Thus, the transplanted kidney itself rather than the recipient determines the susceptibility to acute cyclosporine-induced nephrotoxicity.

Pharmacokinetics of fleroxacin after multiple oral dosing in patients receiving regular hemodialysis.

The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.