Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1­18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.

The transition from childhood to adulthood with ESRD: educational and social challenges.

OBJECTIVE: The purpose of this review was to examine potential barriers to adulthood transition for children and adolescents with chronic kidney disease (CKD). RESULTS: The literature was reviewed in regards to medical, neuropsychological, psychiatric and psychosocial barriers that may impede successful transition. Adults with CKD since childhood have been found to be at increased risk for neurocognitive impairment, low educational attainment, unemployment, psychiatric disability, and psychosocial adjustment. CONCLUSION: Based on the available literature, intervention strategies are discussed in addition to directions for future research.

Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells.

Adenosine produces a wide variety of physiological effects through the activation of specific adenosine receptors (A(1), A(2A), A(2B), A(3)). Adenosine, acting particularly at the A(2A) adenosine receptor (A(2A)AR), is a potent endogenous anti-inflammatory agent and sensor of inflammatory tissue damage. The complete healing of wounds is the final step in a highly regulated response to injury. Recent studies on epidermal wounds have identified the A(2A)AR as the main adenosine receptor responsible for altering the kinetics of wound closure. We hypothesized that A(2A)AR promotes wound healing in bronchial epithelial cells (BECs). To test this hypothesis, the human BEC line BEAS-2B and bovine BECs (BBECs) were used. Real-time RT-PCR of RNA from unstimulated BEAS-2B cells revealed transcriptional expression of A(1), A(2A), A(2B) and A(3) receptors. Western blot analysis of lysates from BEAS-2B cells and BBECs detected a single band at 44.7 kDa in both the BECs, indicating the presence of A(2A)AR. In a wound healing model, we found that adenosine stimulated wound repair in cultured BBECs in a concentration-dependent manner, with an optimal closure rate observed between 4 and 6 h. Similarly, the A(2A)AR agonist 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA) augmented wound closure, with a maximal closure rate occurring between 4 and 6 h. Inhibition of A(2A)AR with ZM-241385, a known A(2A)AR antagonist, impeded wound healing. In addition, ZM-241385 also attenuated adenosine-mediated wound repair. Kinase studies revealed that adenosine-stimulated airway repair activates PKA by ligating A(2A)AR. Collectively, the data suggest that the A(2A)AR is involved in BEC adenosine-stimulated wound healing and may prove useful in understanding purinergic-mediated actions on airway epithelial repair.

IL-8 inhibits isoproterenol-stimulated ciliary beat frequency in bovine bronchial epithelial cells.

Mucociliary clearance is a critical host defense that protects the lung. The mechanisms by which mucociliary function is altered by inflammation are poorly defined. Chronic exposure to cigarette smoke decreases ciliary beating and interferes with proper airway clearance. Bronchoalveolar lavage (BAL) fluid from smokers and ex-smokers has increased amounts of IL-8, which has played a critical role in airway inflammation. We hypothesized that IL-8 might interfere with stimulated ciliary beating in airway epithelium. To test this hypothesis, we stimulated bovine ciliated bronchial epithelial cells (BBECs) with a known activator of ciliary beat frequency (CBF), isoproterenol (ISO; 100 microM), in the presence or absence of IL-8 (100 pg/mL). We measured CBF digitally using the Sisson-Ammons Video Analysis (SAVA) system. CBF increased in untreated cells exposed to ISO (approximately 3 Hz) over baseline. In contrast, cells pre-incubated with IL-8 failed to respond to ISO. Pretreatment with IL-8 also blocked ISO-stimulated cAMP-dependent kinase (PKA) activation, which is known to control ISO-stimulated CBF. In addition, IL-8 pretreated cells revealed a marked decrease in PKA activity when cells were stimulated with forskolin (FSK; 10 microM). Cells were assayed specifically for cAMP-phosphodiesterase (PDE) activity. ISO-stimulated cells demonstrated an increase in PDE activity as compared to control. Pretreatment with IL-8 had no effect on ISO-stimulated PDE activity. Collectively, these data suggest that IL-8 appears to mediate its effect at the level of adenylyl cyclase. It is also possible that IL-8 may not only act as a chemotactic agent, but also as a potential autocrine/paracrine inhibitor of PKA-mediated stimulation of ciliary motility. In conclusion, IL-8 inhibits beta-agonist dependent ciliostimulation and such inhibition of stimulated ciliary activity may contribute to the impaired mucociliary clearance seen in airway diseases. Furthermore, since IL-8 levels are increased in the airway of cigarette smokers, it is likely they may be more resistant to the cilio and muco-ciliostimulating effects of beta-agonists.

Intraperitoneal administration of recombinant human growth hormone in children with end-stage renal disease.

Recombinant human growth hormone (GH) therapy has been shown to be effective in the treatment of growth failure related to growth hormone resistance among children with chronic renal failure. The traditional route of administration is subcutaneous injection. This study was designed to evaluate the effectiveness and tolerability of intraperitoneal (i.p.) administration of GH in prepubertal peritoneal dialysis patients. Nine subjects were enrolled. Eight completed 24 months of therapy with GH. Baseline height standard deviation scores (SDS) and growth velocity for the prior year were used for comparison. Peak serum GH was achieved 4 h after administration and serum half-life was 4.6 h. Mean height SDS was -3.1 at baseline, -2.5 at 1 year, and -2.3 at 2 years (NS) of GH therapy. Mean height velocity increased from a baseline of 4.6 cm/yr to 8.5 cm/yr in year 1 (P < 0.05) and 6.1 cm/yr in year 2 (NS) of i.p. GH therapy. Peritonitis infection rates were not increased from overall center rates. This research suggests that the intraperitoneal route of administration of GH can be utilized in the treatment of short stature among children requiring maintenance peritoneal dialysis therapy.

Anthropometric measures and risk of death in children with end-stage renal disease.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Cytokines potentiate human eosinophil superoxide generation in the presence of N(omega)-nitro-L-arginine methyl ester.

The eosinophilic (EOS) leukocyte has been implicated as a primary effector cell in inflammatory and allergic diseases. Cytokines are among the mediators of inflammatory and allergic diseases which modulate the effector functions of EOS. Certain cytokines, elevated in patients with various allergies, are thought to modulate EOS reactive oxygen species superoxide anion and nitric oxide (NO) responses. Though EOS transcribe and translate mRNA for inducible NO synthase, the effects of cytokines on NO generation remain largely unknown. Thus, we have investigated effects of IL-3, IL-5, GM-CSF, IL-8, RANTES and the proinflammatory cytokines TNF-alpha and IFN-gamma, on superoxide anion and NO generation by clone 15 HL-60 human eosinophilic cells. Cytokine treatments (3 and 18 h) resulted in production of small amounts of superoxide anion which were enhanced by the NO inhibitor L-NAME. In the presence of L-NAME, PMA (1 nM) stimulation significantly increased superoxide anion generation following 3 h treatments with IL-3, TNF-alpha or IFN-gamma. Eighteen hour cytokine treatments with GM-CSF, IL-8, RANTES, IFN-gamma or TNF-alpha primed the cells for enhanced reactive oxygen species following exposure to an EOS stimulant. Inhibition of NO synthesis resulted in increased levels of superoxide anion. Collectively, these results suggest that an environment of proinflammatory cytokines may potentiate the generation of reactive oxygen species by EOS. These results further suggest that at an inflammatory site or during an allergic response, EOS may concomitantly synthesize NO and generate superoxide anion, fractions of which may rapidly react to form the potent oxidant peroxynitrite.

Prescription of hormone replacement therapy in postmenopausal women with renal failure.

UNLABELLED: Prescription of hormone replacement therapy in postmenopausal women with renal failure. BACKGROUND: Although patients with end-stage renal disease (ESRD) are at increased risk for early menopause, osteoporosis, cognitive dysfunction, and cardiovascular disease, few postmenopausal women are prescribed hormone replacement therapy (HRT). The reasons for the low prescription rate are not known. This study uses data from the United States Renal Data System (USRDS) to assess the prevalence and predictors of HRT use in postmenopausal women with ESRD. METHODS: Data were obtained from the USRDS Dialysis Morbidity and Mortality Study Wave 2. All women who were at least 45 years of age were considered postmenopausal and were selected for our analysis. Demographics, behavior and medical characteristics were abstracted from the database. Logistic regression was used to estimate the independent contribution of population characteristics in predicting the use of HRT. Linear regression models were used to estimate the relationship between HRT use and both triglycerides and total cholesterol. RESULTS: The overall prevalence of HRT prescription was 10.8%. Important predictors of HRT use included age (aOR = 0.74, 95% CI 0.13 to 0.88, P < 0.001), black ethnicity (aOR = 0.50, 95% CI, 0.31 to 0.78, P < 0.002), college education (aOR = 3. 00, 95% CI, 1.70 to 5.24, P < 0.001), and the ability to ambulate (aOR = 1.99, 95% CI, 1.01 to 3.91, P = 0.05). Serum triglyceride and total cholesterol levels were higher among women treated with HRT than among those not treated with HRT (264 +/- 155 vs. 217 +/- 159 mg/dl, P = 0.001 and 220 +/- 62 vs. 209 +/- 55 mg/dl, P = 0.02, respectively). CONCLUSIONS: HRT is prescribed less frequently in postmenopausal ESRD patients than in the general population. Younger age, higher education levels, white race, and the ability to ambulate were important predictors of HRT use. Targeting populations of patients who are likely to benefit from but less likely to be prescribed HRT may increase the prescription of HRT.

Principles of dialysis: special issues in women.

Nephrologists are frequently responsible for the primary care of their female patients. As such, they must be aware of medical issues that are unique to women. Although many of the medical considerations are similar to those in women without renal disease, there are a number of special considerations unique to end-stage renal disease (ESRD) patients. Women comprise a smaller proportion of the dialysis population and have better survival rates than men do. The improved survival is less marked than seen in the general population and may be function of differential susceptibility to disease processes, socio-cultural factors, or gender differences in acceptance or transplantation rates. A variety of factors are important in choosing dialysis modality including lifestyle issues and previous abdominal surgery. Women with ESRD are at high risk of both sexual and gonadal dysfunction, for which the latter may be treated with replacement hormones. Pregnancy is rare and requires an increase in the dose of dialysis and the care of a team of experienced physicians. Finally, awareness and implementation of routine health maintenance recommendations is essential in the care of female dialysis patients.

Regulation of 10P2 murine mast cell proliferation and secretory function by stem cell factor or IL-9.

Mast cells are effectors of inflammatory responses. When triggered by immunological or nonimmunological mechanisms, mast cells release potent biological mediators from preformed stores and synthesize others de novo. In previous investigations from this laboratory, the signal transduction pathways of cloned 10P2 cytokine-independent mast cells were explored. Results suggested that 10P2 cells undergo activation-secretion coupling assessed as release of stored [14C]serotonin (5-HT) when challenged with IgE-specific antigen, influx of extracellular calcium, release of intracellular calcium stores, or by direct activation of protein kinase C isozymes. In the present investigations, cytokine proliferative effects and modulatory roles on release of stored [14C]5-HT have been explored. Following passive sensitization with anti-dinitrophenol (anti-DNP) IgE and challenge with DNP, mast cells released up to 32% of the stored [14C]5-HT. Pretreatment of cells with 10, 30, or 50 ng/ml stem cell factor (SCF) did not alter the response. SCF did not directly induce [14C]5-HT release. Pretreatment with 25 ng/ml interleukin-9 (IL-9) significantly potentiated the IgE-antigen release by 51.1%, 35.7%, or 31.6% when challenged with 3, 10 or 30 ng/ml DNP-HSA. Treatment of cells with 1-100 ng/ml SCF for 72 hr resulted in significantly enhanced proliferation whereas this did not occur when cells were treated with 1-100 ng/ml IL-9. Collectively, these results suggest that SCF alone has a proliferative effect, does not alter the IgE-specific antigen signal transduction pathway, and does not directly stimulate mast cell degranulation. In contrast, IL-9 potentiates the IgE-antigen signal transduction response but exerts no proliferative response. Reports of effects of orally administered cytokines are now beginning to emerge. This raises the possibility that cytokines may be a future therapeutic approach to treatment of allergic and nonallergic inflammatory diseases. The 10P2 cytokine-independent mast cell line may be a valuable adjunct to existing mast cell models as this avenue of drug discovery is explored.

Cardiac angiotensin II receptor populations during aortocaval fistulae, AII and beta adrenergic receptor blockade.

Cardiac angiotensin (AII) receptor subtype expression that occurs during volume overload and beta adrenergic blockade was assessed in male rats pretreated with saline (S) or saralasin (Sar) for 2 weeks. Following pre-treatment, an arteriovenous fistula was produced and some animals were then infused with metoprolol or propranolol for 28 days after which AII binding studies were done. In sham-operated animals, there was more of the AT1 receptor subtype that exhibited more monophasic binding. With fistula, there was biphasic binding, with the AT2 population being the predominate type. Metoprolol or propranolol partially reversed the receptor population shift back to AT1, indicating that the AT2 receptor subtype may play a role in the heart enlargement induced by volume overload and suggesting a functional interrelationship between the beta adrenergic receptors and AII receptors.

A comparison of the effects of buspirone and diazepam on plasma corticosterone levels in rat.

The effect of the anxiolytic agents, buspirone and diazepam, on the hypothalamic-pituitary-adrenal axis (HPAA), indicated by changes in the concentration of corticosterone (CS) in plasma, were studied 1/2, 1, 2, 4, 6, 8 and 24 hr after administration of the drug (i.p.). Samples of plasma were collected in the mid-morning (0930-1130 hr) when activity in the hypothalamic-pituitary-adrenal axis in the rat and control levels of corticosterone were low and were repeated in the afternoon (1400-1600 hr) when activity in the hypothalamic-pituitary-arenal axis and levels of corticosterone were higher. At small doses (1 mg/kg) buspirone had a greater facilitating effect on the hypothalamic-pituitary-adrenal axis than did diazepam. In addition, buspirone had a greater maximum facilitatory effect (477%) on levels of corticosterone than diazepam (345%). However, buspirone (ED50 = 8.6 mumol/kg) and diazepam (ED50 = 8.7 mumol/kg) were equipotent. Administration of 1 mg/kg of buspirone in the morning increased the combined 1/2 and 1 hr circulating levels of corticosterone 75% above control levels. Diazepam, at 1 mg/kg, did not produce any significant changes in levels of corticosterone. Large doses (10 mg/kg) of buspirone increased morning levels of corticosterone by 328% and diazepam increased levels of corticosterone by 265%. During the afternoon small doses of buspirone or diazepam did not significantly alter levels of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)