No abstract

The poor prognosis associated with malignant glioma is largely attributable to its invasiveness and robust angiogenesis. Angiogenesis involves host-tumor interaction and requires in vivo evaluation. Despite their versatility, few studies have employed mouse glioma models with perfusion MRI approaches, and generally lack longitudinal study design. Employing a micro-MRI system (8.5T), a novel dual bolus-tracking perfusion MRI strategy was implemented. Using the small molecule contrast agent Magnevist, dynamic contrast enhanced MRI was implemented in the intracranial 4C8 mouse glioma model to determine Ktrans and ve, indices of tumor vascular permeability and cellularity, respectively. Dynamic susceptibility contrast MRI was subsequently implemented to assess both cerebral blood flow and volume, utilizing the macromolecular superparamagnetic iron oxide, Feridex, which circumvented tumor bolus susceptibility curve distortions from first-pass extravasation. The high resolution parametric maps obtained over 4 weeks, indicated a progression of tumor vascularization, permeability, and decreased cellularity with tumor growth. In conclusion, a comprehensive array of key parameters were reliably quantified in a longitudinal mouse glioma study. The syngeneic 4C8 intracerebral mouse tumor model has excellent characteristics for studies of glioma angiogenesis. This approach provides a useful platform for noninvasive and highly diagnostic longitudinal investigations of anti-angiogenesis strategies in a relevant orthotopic animal model.

<b><i>Background:</i></b> Acute kidney injury (AKI) and intraventricular hemorrhage (IVH) are common in premature infants. We previously demonstrated that infants with AKI have a higher hazards ratio to develop grade ≥2 IVH when controlling for confounders. However, that single-center study was unable to show an overall association. <b><i>Objectives:</i></b> To test the hypothesis that infants diagnosed with AKI have an increased risk of IVH independent of variables associated with both AKI and IVH, we performed a study on 825 infants from the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study (a 24-center multinational retrospective cohort). <b><i>Method:</i></b> A neonatal modified KDIGO definition of AKI was used based on serum creatinine (SCr) and/or urine output criteria. Baseline SCr was defined as the lowest previous value. IVH was diagnosed with head ultrasounds. <b><i>Results:</i></b> AKI was documented in 22.2% (183/825) of infants and IVH in 14.3% (118/825). Infants with AKI (<i>n</i> = 183) were more likely to have IVH (26.8%, 49/183) than those without AKI (<i>n</i>= 642) who had IVH (10.7%, 69/642, <i>p</i> &#x3c; 0.0001). After controlling for 5-min Apgar score, vasopressor support within the first week of age, and gestational age, infants with AKI had 1.6 times higher adjusted odds to develop any grade IVH (95% CI 1.04–2.56). Furthermore, infants of gestational age of 22–28 weeks had 1.9 times higher adjusted odds to develop IVH (OR 1.87, 95% CI 1.08–3.23). <b><i>Conclusions:</i></b> We present the first multicenter evaluation of the association between AKI and IVH in premature infants showing a significant independent association between AKI and IVH. Development of strategies to reduce AKI may also reduce IVH.

Despite improvements in survival of premature infants, many have comorbid conditions. The role of the kidney in multiorgan dysfunction is unclear, particularly in regard to intraventricular hemorrhage (IVH). We hypothesized that infants diagnosed with acute kidney injury (AKI) have an increased risk of IVH independent of gestational age (GA) and other variables associated with both comorbidities. This prospective cohort study consisted of 125 infants with a birth weight ≤1,200 g and/or GA ≤31 weeks. A definition of AKI was used from KDIGO, not including urine output as nonoliguria is common in this population. IVH was based on serial head ultrasounds. Neonates with AKI had a higher trend towards having IVH compared to those without [14/35 (40%) vs. 22/83 (26.5%), p = 0.1]. Infants with AKI were more likely to have stage 2 IVH or higher than those without AKI [12/36 (33.3%) vs. 6/82 (7.3%); p < 0.01]. AKI was associated with a 3.6-fold increased risk of a grade 2 or higher IVH [hazard ratio (HR) 3.55, 95% confidence interval (CI) 1.39-9.07] and over 4-fold increase in risk of a grade 3 or higher IVH (HR 4.34, 95% CI 1.43-13.21). While there was no association between AKI and IVH overall, those with AKI had a higher hazard ratio to develop a grade 2 or higher IVH even when controlling for birth weight, antenatal steroid use, and 5-min Apgar score. Future studies are indicated to expand sample size and to control for other clinical variables that could be associated with both AKI and IVH.