Andrew M. South

Antenatal Corticosteroids and the Renin-Angiotensin-Aldosterone System in Adolescents Born Preterm

Background:Antenatal corticosteroid (ANCS) treatment hastens fetal lung maturity and improves survival of premature infants, but the long-term effects of ANCS are not well-described. Animal models suggest that ANCS increases the risk of cardiovascular disease through programmed changes in the renin-angiotensin (Ang)-aldosterone system (RAAS). We hypothesized that ANCS exposure alters the RAAS in adolescents born prematurely.Methods:A cohort of 173 adolescents born prematurely was evaluated, of whom 92 were exposed to ANCS. We measured plasma and urine Ang II and Ang-(1–7) and calculated Ang II/Ang-(1–7) ratios. We used general linear regression models to estimate the difference in the RAAS between the ANCS-exposed and unexposed groups, adjusting for confounding variables.Results:In unadjusted analyses, and after adjustment for sex, race, and maternal hypertension, ANCS exposure was associated with increased urinary Ang II/Ang-(1–7) (estimate 0.27 (95% CI 0.03, 0.5), P = 0.03), increased plasma Ang-(1–7) (0.66 (0.26, 1.07), P = 0.002), and decreased plasma Ang II/Ang-(1–7) (−0.48 (−0.91, −0.06), P = 0.03).Conclusion:These alterations indicate an imbalance in the urinary RAAS, promoting the actions of Ang II at the expense of Ang-(1–7), which over time may increase the risk of renal inflammation and fibrosis and ultimately hypertension and renal disease.

Transplant immuno-diagnostics: crossmatch and antigen detection.

Identifying and monitoring donor-directed anti-human leukocyte antigen antibodies are a rapidly evolving area of solid organ transplantation. Donor-specific antibodies dictate pre-transplant donor choice and donor–recipient matching and underlie much acute and chronic allograft rejection and loss. The evolution of available technology has driven this progress. Early, labor-intensive, whole-cell assays based on complement-dependent cytotoxicity suffered from poor sensitivity and specificity, technical challenges and lack of precision. Sequential improvement in assay performance included anti-human immunoglobulin-enhanced, complement-dependent cytotoxicity techniques followed by cell-based flow cytometry. However, variable specificity and sensitivity inherent in cell-based testing continued to limit flow cytometry. The introduction of solid-phase assays led to a second revolution in histocompatibility testing with the use of purified antigens bound to artificial surfaces rather than whole cells. These techniques augmented sensitivity and specificity to detect even low-titer antibodies to previously undetected antigens. Identification of complement-activating antibodies is being introduced, but current technology is in the developmental stage. While the detection of alloantibodies has improved dramatically, our comprehension of their importance remains imperfect. Variability in methodology and a lack of standardization limits the clinical application of these tests. In spite of the hurdles that remain, antibody-mediated rejection has become a key target to improve graft survival.

Antenatal corticosteroids and cardio-metabolic outcomes in adolescents born with very low birth weight

BackgroundExposure to antenatal corticosteroids (ANCS) is associated with adverse cardiometabolic outcomes in animal models; however, long-term outcomes in clinical studies are not well characterized. We hypothesized that exposure to ANCS would be associated with markers of increased cardiometabolic risk in adolescents born with very low birth weight (VLBW).MethodsIn an observational cohort of 186 14-year-old adolescents born with VLBW, we measured resting blood pressure (BP), BP response to cold, ambulatory BP, and anthropometrics; performed dual-energy X-ray absorptiometry; and analyzed blood samples for uric acid, cholesterol, glycated hemoglobin, and high-sensitivity C-reactive protein. Multivariate analyses were used to evaluate associations with ANCS, adjusting for race, sex, and maternal hypertensive pregnancy.ResultsThere were no ANCS group differences in BP measures or blood biomarkers. Compared with adolescents unexposed to ANCS, those exposed to ANCS were taller (exposed–unexposed mean difference 3.1 cm (95% confidence interval (CI) 0.7, 5.5)) and had decreased waist-to-height ratio (exposed–unexposed mean difference −0.03 (95% CI −0.058, −0.002)). Males exposed to ANCS had lower total cholesterol (exposed–unexposed mean difference −0.54 mmol/l (95%CI −0.83, −0.06)).ConclusionAmong adolescents born with VLBW, ANCS exposure was not associated with markers of increased cardiometabolic risk.

How Infrastructure Public–Private Partnership Projects Change Over Project Development Phases:

This research adds to work on the development of infrastructure public–private partnership projects (P3s), which is a rapidly growing mode of infrastructure service delivery. Infrastructure P3 projects typically have a long life cycle, but little is understood about the nature of the changes that such a project goes through over the phases of its life cycle. This article contributes to project research as it studies the changes that an infrastructure P3 project goes through over its life cycle and suggests how those changes can be governed over the life cycle of the project. The research is empirically informed from an in-depth case study of a highway transportation P3 in California over a 20-year period. This research shows that the developmental phases of P3s differ by dramatic changes in the composition of stakeholder networks and the use of institutional logic. First, employing social network analysis (SNA), we map the network of stakeholders in the P3 case and show how the stakeholder network changes over four phases. Second, we identify how different stakeholders use formal and informal institutional logic in their interactions, and demonstrate that the dominant institutional logic employed in the P3 changes from informal to formal over the P3’s life cycle. We further show how this change in the P3’s dominant institutional logic corresponds to the dynamism in the stakeholder network. We propose that infrastructure P3s should be analyzed and governed as the dynamic arrangements they are—constellations of stakeholders that change individually and undergo change collectively over a long life cycle of different phases.

Children tolerate intradialytic oral nutrition: PAEDIATRIC INTRADIALYTIC ORAL NUTRITION

BACKGROUND People undergoing haemodialysis (HD) often have poor nutrition, which in turn can contribute to worse outcomes. Inadequate nutrition has a particularly deleterious effect on growth and neurocognitive development, as well as mortality, in children and adolescents. Nutritional supplementation can improve outcomes but can be difficult to administer. OBJECTIVE Determine the tolerability of intradialytic oral nutrition in children and adolescents. DESIGN A cross-sectional quality improvement study in an outpatient paediatric HD unit. Intervention was intradialytic oral nutritional supplementation provided as protein bars and/or meals. SUBJECTS Children and adolescents undergoing outpatient HD who were able to participate in surveys and eat by mouth. MEASUREMENTS Adverse effects and symptoms on nurse- and patient-reported surveys, respectively. Relationships between the predictor variables and the outcomes were assessed using generalised estimating equations. RESULTS The majority of children felt better after eating on dialysis (72%) with no adverse effects (80%). On unadjusted analyses and confirmed with generalised estimating equation modelling, children who reported being hungry felt better after eating on dialysis, despite being more likely to have adverse effects. CONCLUSION The study demonstrates that our children and adolescents feel better after eating on HD with minimal adverse effects. The finding that hungry patients are more likely to feel better despite having a higher likelihood of an adverse effect demonstrates the tolerability of eating on HD. Intradialytic oral nutrition could be a safe and well-tolerated opportunity to provide supplemental nutrition to paediatric HD patients and improve outcomes.

Primary renal diffuse large B-Cell lymphoma causing haemodialysis-dependent nephromegaly in a child

A 4-year-old boy presented with fatigue and was found to have severe kidney injury requiring haemodialysis. A renal ultrasound demonstrated bilateral nephromegaly with mild loss of corticomedullary differentiation but preserved echogenicity. He had a persistent isolated monocytosis. Renal biopsy revealed extensive infiltration by primary renal diffuse large B-cell lymphoma. He required haemodialysis for 18 days and received chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab and intrathecal methotrexate. He achieved remission with an estimated glomerular filtration rate of 50 mL/min/1.73 m2, and his kidneys returned to normal size. Nephromegaly due to renal-limited haematolymphoid disease is extremely rare, especially in children.

Persistent C4d and antibody-mediated rejection in pediatric renal transplant patients

Pediatric renal transplant recipient survival continues to improve, but ABMR remains a significant contributor to graft loss. ABMR prognostic factors to guide treatment are lacking. C4d staining on biopsies, diagnostic of ABMR, is associated with graft failure. Persistent C4d+ on follow‐up biopsies has unknown significance, but could be associated with worse outcomes. We evaluated a retrospective cohort of 17 pediatric renal transplant patients diagnosed with ABMR. Primary outcome at 12 months was a composite of ≥50% reduction in eGFR, transplant glomerulopathy, or graft failure. Secondary outcome was the UPCR at 12 months. We used logistic and linear regression modeling to determine whether persistent C4d+ on follow‐up biopsy was associated with the outcomes. Forty‐one percent reached the primary outcome at 12 months. Persistent C4d+ on follow‐up biopsy occurred in 41% and was not significantly associated with the primary outcome, but was significantly associated with the secondary outcome (estimate 0.22, 95% CI 0.19‐0.25, P < .001), after controlling for confounding factors. Persistent C4d+ on follow‐up biopsies was associated with a higher UPCR at 12 months. Patients who remain C4d+ on follow‐up biopsy may benefit from more aggressive or prolonged ABMR treatment.

A Hyperpigmented Reticular Rash in a Patient on Peritoneal Dialysis

Chronically ill patients often develop uncommon exam findings. A 16-year-old female with end-stage renal disease secondary to immune complex-mediated glomerulonephritis on peritoneal dialysis (PD) developed a pruritic, hyperpigmented reticular rash on her abdomen, sparing the PD catheter insertion site. The rash appeared approximately 6 weeks after initiating PD. She used a heating pad nightly during PD for dialysis drain pain. Testing for systemic and autoimmune disease was negative. She was referred to dermatology, where the diagnosis of erythema ab igne (EAI), a well-described but less well-known hyperpigmented reticular cutaneous eruption caused by chronic exposure to low levels of infrared heat, was confirmed. The eruption is typically painless but is often pruritic. Common sources of heat include fires, stoves, portable heaters, heating pads, and laptop computers. The association between EAI and PD is unknown. Our patient discontinued the heating pad and her rash resolved.