Effect of hypertension on the progression of chronic renal failure in children

This article reviews the current state of knowledge concerning the vicious cycle of hypertension and progressive loss of renal function in renal disease, as well as the renoprotective potential of antihypertensive treatment, with a specific focus on children and adolescents. Deficient arteriolar autoregulation renders damaged kidneys particularly sensitive to systemic high blood pressure (BP). Intraglomerular hypertension promotes proteinuria, which further activates the renin-angiotensin system (RAS). Angiotensin II, apart from its vasoconstrictor effects, induces local proinflammatory and profibrotic signaling molecules resulting in renal scarring. The activity of the scarring process with the resultant loss of functional renal mass appears to be modulated, in part, by a polymorphism in the angiotensin converting enzyme (ACE) gene. Clinical studies in adults have demonstrated convincingly the high risk of progression of chronic renal failure (CRF) associated with high BP, the benefit of lowering BP to even the low normal range, and the specific benefit of drugs that inhibit the RAS on the progression of CRF. In children, even moderately elevated BP and moderate proteinuria have been shown to be significant risk factors for progression and CRF. The optimal target BP for children with CRF is currently being determined in a multinational, randomized, prospective tria

Cyclosporine absorption profiles in pediatric kidney and liver transplant patients

Cyclosporine absorption profiling uses either the area under the concentration curve in the first 4 h post dose, AUC(0–4), or the concentration 2 h post dose (C2) to optimize immunosuppression in adult kidney and liver transplantation. We characterized C2 versus AUC(0–4) relationships over time after transplant and across transplant indications in 56 pediatric transplant patients. There were 36 kidney transplant patients aged 9.7±3.9 years. Nineteen of these patients were studied in the de novo period on day 7 post transplant and 17 in the maintenance phase more than 1 year post transplant. In addition, 20 liver transplant patients aged 8.9±4.2 years were studied in the maintenance phase. All patients had five blood samples collected over the 12-h dose interval that were analyzed by validated assay methods at a central laboratory. Pediatric C2 values were 1,463±658 ng/ml for de novo kidney, 954±322 ng/ml for maintenance kidney, and 619±339 ng/ml for maintenance liver transplant patients. C2 was a strong predictor of AUC(0–4) in all three pediatric groups, with coefficients of determination ( r 2 ) ranging from 0.861 to 0.936. Although data were limited from the de novo period, the C2 versus AUC(0–4) regression was consistent over time after transplant and between transplant indications, with a regression slope of 2.50 in de novo kidney, 2.54 in maintenance kidney, and 2.76 in maintenance liver transplant recipients. These slopes were also comparable to that in adult maintenance kidney transplant patients (2.60). In conclusion, C2 versus AUC(0–4) relationships demonstrated consistency over time (de novo vs. maintenance phase), between transplant indications (kidney vs. liver), and across age groups (pediatric vs. adult patients). Average C2 values achieved with current pediatric cyclosporine dosing practices cluster around the target C2 ranges recommended for adults.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47821/1/467_2003_Article_1260.pd

The Designed Ankyrin Repeat Protein Antiviral Ensovibep for Nonhospitalized Patients With Coronavirus Disease 2019: Results From EMPATHY, a Randomized, Placebo-Controlled Phase 2 Study

Background: The coronavirus disease 2019 (COVID-19) pandemic was characterized by rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, affecting viral transmissibility, virulence, and response to vaccines/therapeutics. EMPATHY (NCT04828161), a phase 2 study, investigated the safety/efficacy of ensovibep, a multispecific designed ankyrin repeat protein (DARPin) with multivariant in vitro activity, in ambulatory patients with mild to moderate COVID-19. Methods: Nonhospitalized, symptomatic patients (N = 407) with COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600 mg) or placebo and followed until day 91. The primary endpoint was time-weighted change from baseline in log10 SARS-CoV-2 viral load through day 8. Secondary endpoints included proportion of patients with COVID-19-related hospitalizations, emergency room (ER) visits, and/or all-cause mortality to day 29; time to sustained clinical recovery to day 29; and safety to day 91. Results: Ensovibep showed superiority versus placebo in reducing log10 SARS-CoV-2 viral load; treatment differences versus placebo in time-weighted change from baseline were -0.42 (P =. 002), -0.33 (P =. 014), and -0.59 (P <. 001) for 75, 225, and 600 mg, respectively. Ensovibep-treated patients had fewer COVID-19-related hospitalizations, ER visits, and all-cause mortality (relative risk reduction: 78% [95% confidence interval, 16%-95%]) and a shorter median time to sustained clinical recovery than placebo. Treatment-emergent adverse events occurred in 44.3% versus 54.0% of patients in the ensovibep and placebo arms; grade 3 events were consistent with COVID-19 morbidity. Two deaths were reported with placebo and none with ensovibep. Conclusions: All 3 doses of ensovibep showed antiviral efficacy and clinical benefits versus placebo and an acceptable safety profile in nonhospitalized patients with COVID-19