Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease.

Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10.0 and 12.5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1.0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0.16 g/dl and 0.15 g/dl, respectively, with a difference of 0.31 g/dl (95% CI: -0.45, 1.07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.

Ethical issues associated with conducting genetic family studies of complex disease.

PURPOSE: To examine subjects' recognition of the risks and ethical issues associated with enrollment in genetic family studies (GFS) and explore how this recognition affects their informed and voluntary participation. METHODS: A cross-sectional study design including both quantitative and qualitative data was employed. Structured interviews using the Contextual Assessment Approach Questionnaire (CAA-Q) were conducted with 246 Mexican American (MA) participants. To gain in-depth understanding of questionnaire responses, semi-structured interviews with 30 participants were conducted. All participants were interviewed before their enrollment in the Family Investigation of Nephropathy and Diabetes (FIND). RESULTS: Subjects' average age was 56 years; 62% were females. Seventy-eight percent of participants were not formally educated beyond high school and 72% reported an annual household income of < or =20,000 dollars. Eighty-five percent agreed to provide researchers with information on relatives' ages, gender, and education. Sixty-five percent of participants were willing to provide identifiable information such as names, addresses, and phone numbers of relatives. Sixty-three percent of participants indicated that there were direct benefits (i.e., supporting research) to disclosing relatives' information. Seventy-six percent stated that there were no risks associated with participation in GFS (e.g., discrimination or confidentiality of genetic information) compared with 10% who said that there were such risks. While discussing potential risks, subjects did not consider these to influence their decision to participate. CONCLUSIONS: Subjects enrolled in GFS did not recognize and tended to underestimate the social and cultural risks associated with their participation in GFS. If subjects do not fully comprehend the risks, this raises questions concerning their ability to provide informed consent and to voluntarily participate. We propose a subject-centered approach that views enrollment as an active process in which subjects and recruiters give and receive information on risks and ethical issues related to participation, which enhances protection of the rights and welfare of subjects participating in GFS.

Fibronectin induces ureteric bud cells branching and cellular cord and tubule formation.

BACKGROUND: The extracellular matrix (ECM) protein fibronectin is involved in several stages of embryogenesis. Fibronectin exerts its effect through interaction with cellular integrin and nonintegrin receptors. METHODS: We investigated the effect of fibronectin on branching and tubulogenesis of ureteric bud cells in a three-dimensional gel culture system. Primary ureteric bud cells from mouse embryos at gestation 11 days (E11) were isolated and established in culture. Fibronectin and integrin subunits were localized using immunoperoxidase staining. RESULTS: In three-dimensional collagen type I gel culture of ureteric bud cell, fibronectin dose dependently induces cord and tubule formation. Both ureteric bud cells and ureteric bud branches in embryonic kidney express the same multiple integrin subunits that include beta(1), beta(3), alpha(3), alpha(4) and alpha(v). Embryonic kidneys examined at E12, E14, and E16 days of gestation express fibronectin in the undifferentiated mesenchyme especially next to ureteric bud branches and in the interstitium around glomerulotubular structures and blood vessels. Fibronectin expression was similar at the tips and stalks of branching ureteric bud. Fibronectin expression is maximum at E12 and decreases with advanced gestation. Cultured ureteric bud cells also express fibronectin. RGD peptides inhibit cord and tubular formation in the three-dimensional gel. Anti-alpha(3)beta(1) antibody partially inhibits fibronectin-induced cord and tubule formation. Hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and glial cell line-derived neurotrophic factor (GDNF) induce ureteric bud cell cord formation in three-dimensional gel. The effects of growth factors are delayed and quantitatively less compared to the effect of fibronectin. CONCLUSION: Fibronectin induces ureteric bud cells branching and tubulogenesis through interaction with multiple integrin receptors. Cultured ureteric bud cells express fibronectin and the origin of fibronectin at mesenchyme-ureteric bud interface is likely both the metanephric mesenchyme and ureteric bud epithelium. Addition of individual neutralizing antibodies to beta(1), beta(3), alpha(3), alpha(4,)alpha(6) and alpha(v) integrin subunits does not block the effect of fibronectin. Only an antibody to alpha(3)beta(1) integrin substantially blocks the effect of fibronectin. Other mechanisms, including unidentified integrins, are likely involved in fibronectin-induced cord and tubule formation.

Incorporating the Contextual Assessment Approach to regimens used in genetic family studies.

PURPOSE: To develop a procedure that enhances enrollment and addresses ethical issues associated with participation in genetic family studies. METHODS: The Contextual Assessment Approach (CAA) was standardized to the recruitment procedures in the Family Investigation of Nephropathy and Diabetes (FIND) study at the University of Texas Health Science Center at San Antonio. Structured interviews with the CAA questionnaire (CAA-Q) were conducted with 50 low-income Mexican-American probands. The CAA allows systematic interpretation of health beliefs, family dynamics, and attitudes regarding participation in FIND. Data analyses included qualitative and quantitative methods. RESULTS: CAA analyses of probands' perspectives regarding relatives' enrollment in FIND facilitated recruiting 34 probands from whom 30 families were enrolled (family enrollment rate: 88%). CAA reduced recruitment efforts by 32% and avoided exerting undue pressure on unwilling participants to ensure voluntary participation. Remarkably, 76% of the subjects were unaware of any risk associated with participation in genetic family studies. CONCLUSIONS: Administering the CAA-Q before enrolling subjects in FIND increased our enrollment rate by targeting efforts toward the willing subjects and addressing ethical issues associated with their participation.