Microalbuminuria in patients with cystic fibrosis

OBJECTIVE

We previously found that microalbuminuria (MA) is present in 14% of patients with long-standing cystic fibrosis–related diabetes (CFRD). However, others have reported much higher rates of MA in CF patients with and without diabetes (32–67%), suggesting this test is not sufficiently specific for diabetic nephropathy screening in CF. We investigated transient (TMA) and persistent (PMA) microalbuminuria in CF patients to resolve these contradictory findings.

RESEARCH DESIGN AND METHODS

We reviewed 1,449 outpatient urinary albumin measurements from 467 patients aged ≥10 years, which were collected over a decade. TMA was defined as a single episode of MA that subsequently was resolved. PMA was defined as two consecutive or two out of three consecutive measurements in the MA range.

RESULTS

The prevalence of TMA that subsequently was resolved in CF patients was similar to the general population. It was found in 7.6% of patients, including 5% of youth (aged 10–17 years) and 9% of adults. PMA was found in 6.1% of the overall CF population, including 2% of youth and 8% of adults. The odds of PMA were increased sevenfold in patients with CFRD (95% CI 2.5–20, P = 0.0002) and 48-fold in patients with both CFRD and organ transplant (95% CI 13–177, P < 0.0001). The five patients with PMA in the absence of CFRD or transplant included two youths with presumed benign orthostatic MA and three adults with hypertension.

CONCLUSIONS

The spot urine albumin-to-creatinine ratio is specific enough to be a valid screening test for diabetic kidney disease in CFRD.Annual urine albumin screening is recommended for people with type 1 and type 2 diabetes to detect early evidence of diabetic kidney disease (1). Elevated urine albumin is also found in patients with cystic fibrosis–related diabetes (CFRD) (2–6). In a study of 192 CFRD patients, we previously reported that microalbuminuria (MA) was present in 14% of those with long-standing (>10 years) CFRD and, as in the general diabetic population, was associated with worse glycemic control (2). Two other groups, however, have questioned the validity of this association because they found MA to be far more common in CF, even in patients without diabetes (7,8). Dobson et al. (7) reported that MA was present in 67% of single urine samples from six CF patients with diabetes and in 32% of 34 samples from CF patients without diabetes. Another European study (8) found a 58% prevalence of MA in 112 children with CF, none of whom had diabetes. Thus, it was suggested that urine albumin excretion (UAE) may not be specific enough to be used as a screening measure for the detection of diabetic kidney disease in CFRD.The current study attempts to resolve these contradictory findings by determining the prevalence of both transient and persistent MA in CF patients with and without diabetes during routine screening at a large pediatric and adult CF center.     

Improving outcomes in patients with cystic fibrosis

Cystic fibrosis (CF) is the most common fatal inherited disease in Caucasian people. Inheritance follows an autosomal recessive pattern. Recent data indicate that there are more than 9,000 patients with CF in the UK. At a cellular level there is an abnormal CF transmembrane conductance regulator (CFTR), a protein essential for chloride and sodium homoeostasis, caused by a mutation in the CF gene. The consequence of this abnormal protein is thick, viscous secretions in the lungs and GI tract, which lead to recurrent lung infections and pancreatic insufficiency with intestinal malabsorption. Most patients present in early childhood with classic CF. They show one or more of the typical CF phenotypic characteristics (chronic pulmonary disease, GI symptoms and malabsorption, nutritional abnormalities and sinus disease). A minority of patients have atypical CF. They tend to present at an older age, often in adulthood, are mainly pancreatic sufficient, have milder disease and a better prognosis. When CF is suspected the diagnosis can be confirmed by measuring sweat chloride concentration and by looking for CFTR mutations. Immunoreactive trypsinogen is measured in blood taken from a heel prick in all neonates, and is a marker of pancreatic injury consistent with (but not specific for) CF.     

Cephalexin pharmacokinetics in patients with cystic fibrosis

Pharmacokinetics of cephalexin were studied in 7 pediatric and 4 adult patients with cystic fibrosis (CF) and 4 normal adult volunteers. Cephalexin, 250-500 mg, was given as a single dose in suspension. The area under the cephalexin serum concentration-time curve normalized for dose per kilogram averaged 0.185, 0.242, and 0.272 ml/min/kg-1 in pediatric CF patients, adult CF patients, and normal adults, respectively (p greater than 0.05). A threefold interindividual variation was observed in cephalexin renal clearance in CF patients. Renal clearance of cephalexin averaged 5.85 ml/min/kg in pediatric and 4.61 ml/min/kg in adult CF patients (p greater than 0.05). Elimination half-life of cephalexin averaged 0.74, 0.76, and 1.04 h in pediatric patients, adult patients, and normal adults (p greater than 0.05). Cephalexin was well absorbed based on a mean 24-hour urinary recovery of 89 and 93% in pediatric and adult patients. A trend for higher renal clearance of cephalexin was observed among pediatric compared to adult patients. These results indicate that clearance of cephalexin may not increase in patients with CF of minimal severity characterized by an excellent Shwachman score.     

Pharmacodynamics of tobramycin in patients with cystic fibrosis

Relationships between pharmacodynamic indices (PI), such as the area under the concentration-time curve (AUC)/MIC ratio and time > MIC (T(>MIC)), and efficacy have been described for antimicrobial drugs. The use of these quantitative relationships may increase the power to demonstrate significant effects of drugs, obviating the need to include large numbers in comparative trials. Patients with cystic fibrosis (CF) hospitalized for treatment of an infectious exacerbation due to Pseudomonas aeruginosa were eligible for the study. They received tobramycin 3.3 mg/kg tid as initial therapy in combination with ticarcillin 125 mg/kg qid. Blood samples were drawn at t = 0-8 h after infusion. Pharmocokinetic parameters and PI were calculated for every individual and correlated to the relative improvement in forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC) between pretreatment and days 9-11 as a measure of efficacy. The 3 PI fAUC/MIC, f Peak/MIC, and T(>MIC) of tobramycin showed a significant correlation with effect and was the highest for the fAUC/MIC relationships with FEV1 and FVC as determined both by the Emax model as well as Spearman correlations (r = 0.77, P = 0.002 and 0.58, P = 0.036 for FEV1 and FVC). Pharmacokinetic parameters AUC and Peak as such showed no significant correlation with effect, nor did the MIC values. There is a significant relationship between PI of aminoglycosides and efficacy parameter (increase in FEV1 and FVC) in patients with CF. This study demonstrates the applicability of pharmacodynamic relationships in determining efficacy of antimicrobial therapy, by demonstrating a strong PI-effect relationship in a group of only 13 patients.     

Serum sulfate levels in patients with cystic fibrosis

Patients with cystic fibrosis (CF) secrete copious amounts of mucous material which is viscous, tends to accumulate in the respiratory tract and contains larger than normal amounts of sulfate. The present investigation was designed to measure sulfate levels in the serum of patients with cystic fibrosis by ion chromatography of protein-free serum aliquots. The level of inorganic sulfate in the serum of non-cystic fibrosis pediatric patients averaged 0.29 ± 0.03 mmol/l while patients suffering from cystic fibrosis had an average serum sulfate value of 0.27 ± 0.03 mmol/l which was not significantly different from controls. No differences were observed in serum sulfate levels among males and females of either group of patients. There was a tendency for serum sulfate levels to decrease with age, but there was no statistically significant difference in serum sulfate levels between cystic fibrosis patients and normals as a function of age. These findings indicate that the highly sulfated mucoid materials secreted by cystic fibrosis patients are not reflected in abnormal serum sulfate levels.     

Azlocillin pharmacokinetics in patients with cystic fibrosis.

The pharmacokinetics of azlocillin were studied in 10 cystic fibrosis patients, ranging in age from 11 to 28 years. The patients received a 9- to 23-day course of 350 mg of azlocillin per kg in four or six divided daily doses in combination with am aminoglycoside. Blood and urine samples were collected at specified times after the last dose of the course of azlocillin therapy and then assayed for azlocillin content. Pharmacokinetic parameters were determined by noncompartmental analysis. Mean values for serum half-life (1.74 h), disposition constant (0.41 h-1), total body clearance (123 ml/kg per h), and renal clearance (58 ml/kg per h) were determined. All patients exhibited improvement with respect to clinical and laboratory parameters and displayed no adverse reactions. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination, but elimination did not appear to be altered in cystic fibrosis patients.     

Skeletal muscle strength in patients with cystic fibrosis

Little information is available about the role of skeletal muscle strength, including inspiratory and peripheral muscles, in patients with cystic fibrosis (CF). In this study, we evaluated inspiratory and peripheral muscle strength and their relationship with nutritional status and pulmonary function. We assessed forced expiratory volume in one second (FEV₁), inspiratory muscle strength (Pimax), peripheral muscle strength of the knee extensors and elbow flexors, body mass index (BMI), and lean body mass (LBM) in 22 patients in a stable condition. Mean (SD) age was 19 (5) years; FEV₁ was 62 (28) percent predicted; inspiratory muscle strength was 118 (23) percent predicted; knee extensor strength was 80 (23) percent predicted; and elbow flexor strength 76 (21) percent predicted. Mean (SD) BMI was 19.5 (2.8) kg/m² and LBM was 46.4 (10) kg. FEV₁ (percent predicted) was significantly correlated with percent predicted inspiratory muscle strength (r = 0.53; p = 0.011), percent predicted knee extensor strength (r = 0.70, p &lt; 0.001 ), and percent predicted elbow flexor strength (r = 0.62, p = 0.002). These results show that, despite a moderate relationship with FEV₁, inspiratory muscle strength was preserved in our CF patients. Peripheral muscle strength was reduced in those patients with airflow obstruction. Future intervention should focus on the influence of reduced peripheral muscle strength on exercise performance in CF patients.     

Linezolid pharmacokinetics in adult patients with cystic fibrosis

The pharmacokinetics of many drugs are altered in patients with cystic fibrosis (CF), often necessitating different dosage requirements than those used in non-CF patients. The objective of this study was to determine the pharmacokinetics of linezolid, an antibiotic with good activity against gram-positive organisms such as methicillin-resistant Staphylococcus aureus, in patients with CF so that dosage requirements could be established. Twelve adult patients (6 male) ranging in age from 22 to 39 years were studied. A single 600-mg dose was administered intravenously over 0.5 h, and plasma samples were collected at 0 (predose), 0.5, 0.75, 1, 2, 4, 8, and 24 h. Linezolid concentrations were determined with a validated high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using standard noncompartmental methods. Blood chemistry and hematologic indices were determined before and after the study for safety purposes. All patients completed the study without encountering any adverse reactions. The pharmacokinetic parameters, while variable, with half-lives varying from 1.76 to 8.36 h, were similar to those previously described in other populations. Mean (+/- standard deviation) values for pharmacokinetic parameters of interest were as follows: elimination rate constant, 0.21 (0.11) h(-1); half-life, 4.41 (2.43); volume of distribution at steady state, 0.87 (0.19) liters/kg of body weight; and total body clearance, 0.12 (0.06) liters/h/kg. No patient would have achieved the pharmacodynamic target of an area under the concentration-time curve/MIC ratio of 83 h for pathogens for which the MIC was 4 micro g/ml. Patients with inadequate clinical responses to linezolid may require more frequent dosing.     

Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis

The single-dose pharmacokinetics of cefsulodin were evaluated in 12 patients with cystic fibrosis. Each patient received 3 g of cefsulodin intravenously over 30 min. Multiple plasma and urine samples were obtained during the 6-h study period for the determination of cefsulodin. Pharmacokinetic parameters were determined by model-independent methods. Mean values for t1/2, Vss, and CLp were 1.53 h, 0.242 liters/kg, and 117.3 ml/min per 1.73 m2, respectively. Six-hour urine recovery revealed 73.2% of the administered dose with a corresponding cefsulodin urinary clearance of 75.1 ml/min. These pharmacokinetic data in patients with cystic fibrosis appear consistent with data reported for unaffected individuals.     

Pharmacokinetics of inhaled colistin in patients with cystic fibrosis

OBJECTIVES: Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile. PATIENTS AND METHODS: We performed a multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin. RESULTS: Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3+/-1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems. CONCLUSIONS: The low systemic and high local concentrations of colistin support the use of inhaled colistin in CF patients infected with P. aeruginosa.     

Altered disposition of fleroxacin in patients with cystic fibrosis

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.     

Serum bile acid composition in patients with cystic fibrosis

Serum bile acid composition was examined in detail using capillary column gas chromatography and mass spectrometry in 10 children with cystic fibrosis (CF) and 4 healthy children. The mean total bile acid concentration in fasting serum of CF patients was 2.33 +/- 0.84 mumol/l, slightly lower than but not statistically significantly different from healthy controls (mean 2.86 +/- 0.98 mumol/l) and appeared to show no relationship to the degree of exocrine pancreatic insufficiency. Analysis of individual serum bile acids in these children showed that cholic acid represented less than 10% of the total bile acids. Chenodeoxycholic acid was the predominant serum bile acid; the mean concentration in CF patients was 0.98 +/- 0.51 mumol/l, lower than for the healthy controls (1.69 +/- 0.84 mumol/l). Concentrations of lithocholic acid, 3 beta-hydroxy-5-cholenoic, ursodeoxycholic and 3 beta, 7 alpha, 12 alpha-trihydroxy-5 beta-cholanoic acids in fasting serum samples of the CF patients were not significantly different from the healthy control sera but were higher than those normally found in adults. Measurements of fecal bile acid excretion indicated an increased loss of primary bile acids in patients with CF consistent with an impairment of the enterohepatic circulation of bile acids.     

Transglutaminase in erythrocytes of cystic fibrosis patients

Transglutaminase activity was determined in erythrocytes from patients with cystic fibrosis and control subjects. No differences were observed between the two groups either for enzymatic activity or for the activating effect of calcium ions. The previously described abnormal metabolism of polyamines in cystic fibrosis cannot be related to an altered function of transglutaminases.     

Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis

OBJECTIVE: To assess the pharmacokinetics of itraconazole and hydroxy-itraconazole in patients with cystic fibrosis. METHODS: Patients were divided into those <16 and >/=16 years of age. All received itraconazole oral solution 2.5 mg/kg twice daily for 14 days. Serial blood samples were taken for itraconazole and hydroxy-itraconazole plasma level measurements. Safety was assessed from biochemistry and haematology data and reported adverse events. RESULTS: Seventeen patients entered the study. Steady-state concentrations were achieved after maximally 8 days of dosing. On day 14 average peak plasma concentrations were 404 +/- 268 ng/mL (<16 years, n = 5) and 779 +/- 470 ng/mL (>/=16 years, n = 11 excluding one patient concurrently receiving oral clarithromycin). A high inter-subject variability in itraconazole pharmacokinetics was seen. Intra-subject variability was low. All the younger patients and 50% of the older patients failed to achieve a plasma steady-state trough concentration of >250 ng/mL. Adverse events were reported by 53% of subjects. Most were mild or moderate in intensity and not considered related to treatment. One patient withdrew from the study because of two severe adverse events. Ten significant laboratory abnormalities were reported in seven of 16 patients with paired data. Six of these were clinically relevant. CONCLUSION: 2.5 mg/kg itraconazole oral solution twice daily in patients with cystic fibrosis achieves steady-state concentrations in maximally 8 days. The pharmacokinetics showed marked inter-subject variability. Plasma concentrations of >250 ng/mL were not reached in the paediatric cohort or in 50% of the adult cohort. The dosage regimen was safe and well tolerated.     

Evaluation of bronchial drainage in patients with cystic fibrosis.

Examined in this study are the results of six tests of pulmonary function immediately preceding and following bronchial drainage in twenty-six patients with cystic fibrosis. Highly significant increases averaging 5.67, 4.13, 13.47, and 6.98 percent occurred in peak expiratory flow rate, forced vital capacity, expiratory reserve volume, and inspiratory capacity respectively. Significant increases in peak expiratory flow rate, forced vital capacity, and inspiratory capacity were observed in a subgroup of six of the above patients who had evidence of bronchospasm. The authors conclude that bronchial drainage will produce significant increases in routine pulmonary function values. The results suggest that this treatment is most effective in clearing the larger, more proximal, airways and is of benefit even in the presence of clinical bronchospasm.