Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study.

Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75 th percentile), mid- (75 th -90 th percentile) and high-risk (>90 th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.

Non-immunosuppressive treatment for IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease, with approximately 20% to 40% of patients progressing to kidney failure within 25 years. Non-immunosuppressive treatment has become a mainstay in the management of IgAN by improving blood pressure (BP) management, decreasing proteinuria, and avoiding the risks of long-term immunosuppressive management. Due to the slowly progressive nature of the disease, clinical trials are often underpowered, and conflicting information about management with non-immunosuppressive treatment is common. This is an update of a Cochrane review, first published in 2011. OBJECTIVES: To assess the benefits and harms of non-immunosuppressive treatment for treating IgAN in adults and children. We aimed to examine all non-immunosuppressive therapies (e.g. anticoagulants, antihypertensives, dietary restriction and supplementation, tonsillectomy, and herbal medicines) in the management of IgAN. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to December 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using random-effects meta-analysis. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review includes 80 studies (4856 participants), of which 24 new studies (2018 participants) were included in this review update. The risk of bias within the included studies was mostly high or unclear for many of the assessed methodological domains, with poor reporting of important key clinical trial methods in most studies. Antihypertensive therapies were the most examined non-immunosuppressive therapy (37 studies, 1799 participants). Compared to placebo or no treatment, renin-angiotensin system (RAS) inhibition probably decreases proteinuria (3 studies, 199 participants: MD - 0.71 g/24 h, 95% CI -1.04 to -0.39; moderate certainty evidence) but may result in little or no difference to kidney failure or doubling of serum creatinine (SCr), or complete remission of proteinuria (low certainty evidence). Death, remission of haematuria, relapse of proteinuria or > 50% increase in SCr were not reported. Compared to symptomatic treatment, RAS inhibition (3 studies, 168 participants) probably decreases proteinuria (MD -1.16 g/24 h, 95% CI -1.52 to -0.81) and SCr (MD -9.37 µmol/L, 95% CI -71.95 to -6.80) and probably increases creatinine clearance (2 studies, 127 participants: MD 23.26 mL/min, 95% CI 10.40 to 36.12) (all moderate certainty evidence); however, the risk of kidney failure is uncertain (1 study, 34 participants: RR 0.20, 95% CI 0.01 to 3.88; very low certainty evidence). Death, remission of proteinuria or haematuria, or relapse of proteinuria were not reported. The risk of adverse events may be no different with RAS inhibition compared to either placebo or symptomatic treatment (low certainty evidence). In low certainty evidence, tonsillectomy in people with IgAN in addition to standard care may increase remission of proteinuria compared to standard care alone (2 studies, 143 participants: RR 1.90, 95% CI 1.45 to 2.47) and remission of microscopic haematuria (2 studies, 143 participants: RR 1.93, 95% CI 1.47 to 2.53) and may decrease relapse of proteinuria (1 study, 73 participants: RR 0.70, 95% CI 0.57 to 0.85) and relapse of haematuria (1 study, 72 participants: RR 0.70, 95% CI 0.51 to 0.98). Death, kidney failure and a > 50% increase in SCr were not reported. These trials have only been conducted in Japanese people with IgAN, and the findings' generalisability is unclear. Anticoagulant therapy, fish oil, and traditional Chinese medicines exhibited small benefits to kidney function in patients with IgAN when compared to placebo or no treatment. However, compared to standard care, the kidney function benefits are no longer evident. Antimalarial therapy compared to placebo in one study reported an increase in a > 50% reduction of proteinuria (53 participants: RR 3.13 g/24 h, 95% CI 1.17 to 8.36; low certainty evidence). Although, there was uncertainty regarding adverse events from this study due to very few events. AUTHORS' CONCLUSIONS: Available RCTs focused on a diverse range of interventions. They were few, small, and of insufficient duration to determine potential long-term benefits on important kidney and cardiovascular outcomes and harms of treatment. Antihypertensive agents appear to be the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The benefits of RAS inhibition appear to outweigh the harms in patients with IgAN. The certainty of the evidence of RCTs demonstrating a benefit of tonsillectomy to patients with Japanese patients with IgAN was low. In addition, these findings are inconsistent across observational studies in people with IgAN of other ethnicities; hence, tonsillectomy is not widely recommended, given the potential harm of therapy. The RCT evidence is insufficiently robust to demonstrate efficacy for the other non-immunosuppressive treatments evaluated here.

Focused Ultrasound Blood-Brain Barrier Opening Arrests the Growth and Formation of Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCM) are vascular lesions within the central nervous system, consisting of dilated and hemorrhage-prone capillaries. CCMs can cause debilitating neurological symptoms, and surgical excision or stereotactic radiosurgery are the only current treatment options. Meanwhile, transient blood-brain barrier opening (BBBO) with focused ultrasound (FUS) and microbubbles is now understood to exert potentially beneficial bioeffects, such as stimulation of neurogenesis and clearance of amyloid-ß. Here, we tested whether FUS BBBO could be deployed therapeutically to control CCM formation and progression in a clinically-representative murine model. METHODS: CCMs were induced in mice by postnatal, endothelial-specific Krit1 ablation. FUS was applied for BBBO with fixed peak-negative pressures (PNPs; 0.2-0.6 MPa) or passive cavitation detection-modulated PNPs. Magnetic resonance imaging (MRI) was used to target FUS treatments, evaluate safety, and measure longitudinal changes in CCM growth after BBBO. RESULTS: FUS BBBO elicited gadolinium accumulation primarily at the perilesional boundaries of CCMs, rather than lesion cores. Passive cavitation detection and gadolinium contrast enhancement were comparable in CCM and wild-type mice, indicating that Krit1 ablation does not confer differential sensitivity to FUS BBBO. Acutely, CCMs exposed to FUS BBBO remained structurally stable, with no signs of hemorrhage. Longitudinal MRI revealed that FUS BBBO halted the growth of 94% of CCMs treated in the study. At 1 month, FUS BBBO-treated lesions lost, on average, 9% of their pre-sonication volume. In contrast, non-sonicated control lesions grew to 670% of their initial volume. Lesion control with FUS BBBO was accompanied by a marked reduction in the area and mesenchymal appearance of Krit mutant endothelium. Strikingly, in mice receiving multiple BBBO treatments with fixed PNPs, de novo CCM formation was significantly reduced by 81%. Mock treatment plans on MRIs of patients with surgically inaccessible lesions revealed their lesions are amenable to FUS BBBO with current clinical technology. CONCLUSIONS: Our results establish FUS BBBO as a novel, non-invasive modality that can safely arrest murine CCM growth and prevent their de novo formation. As an incisionless, MR image-guided therapy with the ability to target eloquent brain locations, FUS BBBO offers an unparalleled potential to revolutionize the therapeutic experience and enhance the accessibility of treatments for CCM patients.

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Emerging roles for ITAM and ITIM receptor signaling in microglial biology and Alzheimer's disease-related amyloidosis.

Microglia are critical responders to amyloid beta (Aß) plaques in Alzheimer's disease (AD). Therefore, the therapeutic targeting of microglia in AD is of high clinical interest. While previous investigation has focused on the innate immune receptors governing microglial functions in response to Aß plaques, how microglial innate immune responses are regulated is not well understood. Interestingly, many of these microglial innate immune receptors contain unique cytoplasmic motifs, termed immunoreceptor tyrosine-based activating and inhibitory motifs (ITAM/ITIM), that are commonly known to regulate immune activation and inhibition in the periphery. In this review, we summarize the diverse functions employed by microglia in response to Aß plaques and also discuss the innate immune receptors and intracellular signaling players that guide these functions. Specifically, we focus on the role of ITAM and ITIM signaling cascades in regulating microglia innate immune responses. A better understanding of how microglial innate immune responses are regulated in AD may provide novel therapeutic avenues to tune the microglial innate immune response in AD pathology.

Evidence of increased vascular stiffness and left ventricular hypertrophy in children with cystic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of mortality in chronic kidney disease (CKD). Children with early-onset CKD arguably experience the greatest lifetime CVD burden. We utilized data from the Chronic Kidney Disease in Children Cohort Study (CKiD) to evaluate two pediatric CKD cohorts: congenital anomalies of the kidney and urinary tract (CAKUT) and cystic kidney disease for CVD risks and outcomes. METHODS: CVD risk factors and outcomes including blood pressures, left ventricular hypertrophy (LVH), left ventricular mass index (LVMI), and ambulatory arterial stiffness index (AASI) scores were evaluated. RESULTS: Forty-one patients in the cystic kidney disease group were compared to 294 patients in the CAKUT group. Cystic kidney disease patients had higher cystatin-C levels, despite similar iGFR. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) indexes were higher in the CAKUT group, but a significantly higher proportion of cystic kidney disease patients was on anti-hypertensive medications. Cystic kidney disease patients had increased AASI scores and a higher incidence of LVH. CONCLUSIONS: This study provides a nuanced analysis of CVD risk factors and outcomes including AASI and LVH in two pediatric CKD cohorts. Cystic kidney disease patients had increased AASI scores, higher incidence of LVH, and higher rates of anti-hypertensive medication use which could imply a greater burden of CVD despite similar GFR. Our work suggests that additional mechanisms may contribute to vascular dysfunction in cystic kidney disease, and that these patients may need additional interventions to prevent the development of CVD. A higher resolution version of the Graphical abstract is available as Supplementary information.

In hypertension not treated with medications, renal denervation vs. sham reduced daytime ambulatory SBP at 2 mo.

SOURCE CITATION: Azizi M, Saxena M, Wang Y, et al; RADIANCE II Investigators and Collaborators. Endovascular ultrasound renal denervation to treat hypertension: the RADIANCE II randomized clinical trial. JAMA. 2023;329:651-661. 36853250.

Chronic social defeat alters brain vascular-associated cell gene expression patterns leading to vascular dysfunction and immune system activation.

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA sequencing. Using this isolation technique, we found an enrichment in BVAC populations, including distinct subsets of endothelial and microglial cells. In CSD compared to non-stress, home-cage control, differential gene expression patterns disclosed biological pathways involving vascular dysfunction, vascular healing, and immune system activation. Overall, our work demonstrates a unique technique to study BVAC populations from fresh brain tissue and suggests that neurovascular dysfunction is a key driver of psychosocial stress-induced brain pathology.

The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology.

INTRODUCTION: Mutations in INPP5D, which encodes for the SH2-domain-containing inositol phosphatase SHIP-1, have recently been linked to an increased risk of developing late-onset Alzheimer's disease. While INPP5D expression is almost exclusively restricted to microglia in the brain, little is known regarding how SHIP-1 affects neurobiology or neurodegenerative disease pathogenesis. METHODS: We generated and investigated 5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre mice to ascertain the function of microglial SHIP-1 signaling in response to amyloid beta (Aß)-mediated pathology. RESULTS: SHIP-1 deletion in microglia led to substantially enhanced recruitment of microglia to Aß plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP-1 loss enhanced microglial plaque containment and Aß engulfment when compared to microglia from Cre-negative 5xFAD Inpp5dfl/fl littermate controls. DISCUSSION: These results define SHIP-1 as a pivotal regulator of microglial responses during Aß-driven neurological disease and suggest that targeting SHIP-1 may offer a promising strategy to treat Alzheimer's disease. HIGHLIGHTS: Inpp5d deficiency in microglia increases plaque-associated microglia numbers. Loss of Inpp5d induces activation and phagocytosis transcriptional pathways. Plaque encapsulation and engulfment by microglia are enhanced with Inpp5d deletion. Genetic ablation of Inpp5d protects against plaque-induced neuronal dystrophy.

The earliest dipodomyine heteromyid in North America and the phylogenetic relationships of geomorph rodents.

Dipodomyine heteromyids (kangaroo rats and mice) are a diverse group of arid-adapted ricochetal rodents of North America. Here, a new genus and species of a large dipodomyine is reported from early Miocene-aged deposits of the John Day Formation in Oregon that represents the earliest record of the subfamily. The taxon is known from a single specimen consisting of a nearly complete skull, dentary, partial pes, and caudal vertebra. The specimen is characterized by a mosaic of ancestral and highly derived cranial features of heteromyids. Specifically, the dental morphology and some cranial characteristics are similar to early heteromyids, but other aspects of morphology, including the exceptionally inflated auditory bullae, are more similar to known dipodomyines. This specimen was included in a phylogenetic analysis comprising 96 characters and the broadest sampling of living and extinct geomorph rodents of any morphological phylogenetic analysis to date. Results support the monophyly of crown-group Heteromyidae exclusive of Geomyidae and place the new taxon within Dipodomyinae. The new heteromyid is the largest known member of the family. Analyses suggest that large body size evolved several times within Heteromyidae. Overall, the morphology of the new heteromyid supports a mosaic evolution of the open-habitat adaptations that characterize kangaroo rats and mice, with the inflation of the auditory bulla appearing early in the group, and bipedality/ricochetal locomotion appearing later. We hypothesize that cooling and drying conditions in the late Oligocene and early Miocene favored adaptations for life in more open habitats, resulting in increased locomotor specialization in this lineage over time from a terrestrial ancestor.

N-of-1 Trials vs. Usual Care in Children With Hypertension: A Pilot Randomized Clinical Trial.

BACKGROUND: Blood pressure (BP) is often inadequately controlled in children treated for hypertension, and personalized (n-of-1) trials show promise for tailoring treatment choices. We assessed whether patients whose treatment choices are informed by an n-of-1 trial have improved BP control compared to usual care. METHODS: A randomized clinical trial was conducted in a pediatric hypertension clinic in Houston from April 2018 to September 2020. Hypertensive adolescents and young adults 10-22 years old were randomized 1:1 to a strategy of n-of-1 trial using ambulatory BP monitoring to inform treatment choice or usual care, with treatment selected by physician preference. The primary outcome was the proportion of patients with ambulatory BP control at 6 months in a Bayesian analysis. RESULTS: Among 49 participants (23 randomized to n-of-1 trials and 26 to usual care), mean age was 15.6 years. Using skeptical priors, we found a 69% probability that n-of-1 trials increased BP control at 6 months (Bayesian odds ratio (OR) 1.24 (95% credible interval (CrI) 0.51, 2.97), and 74% probability using neutral informed priors (OR 1.45 (95% CrI 0.48, 4.53)). Systolic BP was reduced in both groups, with a 93% probability of greater reduction in the n-of-1 trial group (mean difference between groups = -3.6 mm Hg (95% CrI -8.3, 1.28). There was no significant difference in side effect experience or caregiver satisfaction. CONCLUSIONS: Among hypertensive adolescents and young adults, n-of-1 trials with ambulatory BP monitoring likely increased the probability of BP control. A large trial is needed to assess their use in clinical practice. CLINICALTRIALS.GOV: NCT03461003. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; NCT03461003.

Nocturnal Dipping and Kidney Function Decline: Findings From the CKD in Children Study.

Introduction: Normally, blood pressure (BP) declines by at least 10% from daytime to nighttime. In adults, blunted nocturnal dipping has been associated with more rapid decline in kidney function. Nondipping is prevalent in children with chronic kidney disease (CKD). We sought to determine whether nondipping is associated with proteinuria and progression to kidney failure in children with CKD. Methods: In the prospective CKD in children (CKiD) cohort, Cox proportional hazards models were used to evaluate the relationship between baseline nondipping and progression to kidney failure. Linear mixed effects models were used to evaluate the relationship between nondipping and changes in iohexol glomerular filtration rate (GFR) and urine protein-to-creatinine ratio (log-UPCR, mg/mg) over time. Results: Among 620 participants, mean age was 11 (± 4) years, mean iohexol GFR was 52 (± 22) ml/min per 1.73 m2, and 40% were nondippers at baseline. There were 169 kidney failure events during 2.9 years (median) of follow-up. Dipping status was not significantly associated with kidney failure overall (hazard ratio [HR] 1.08; 95% confidence interval [CI] 0.77, 1.51) or in those with (HR 1.21; 95% CI 0.53, 2.77) or without (HR 1.05; 95% CI 0.71, 1.55) glomerular disease. Dipping status did not modify the relationship between time and change in iohexol GFR or log (UPCR) from baseline (interaction P values = 0.20 and 0.054, respectively). Conclusion: Nondipping is not associated with end-stage kidney disease, GFR decline, or change in proteinuria within the CKiD cohort.

When Hypertension Grows Up: Implications for Transitioning Care of Adolescents and Young Adults With Hypertension From Pediatric to Adult Health Care Providers.

Hypertension (HTN) is an important cause of morbidity and mortality in children as well as adults. HTN and related adverse cardiovascular health develop and progress on a continuum across an individual's life course. Pediatric HTN, or even isolated elevated blood pressure as a child, increases the risk of sustained HTN and cardiovascular disease in later adulthood. Transitioning the care of adolescents and young adults who have HTN is an important but unmet health care need that could potentially have a dramatic effect on mitigating the risk of cardiovascular disease in adulthood. However, very little has been published about the transition process in this population, and considerable gaps in the field remain. We discuss the epidemiology, etiology, and management approach in youth with HTN and how they differ from adults. We contextualize HTN and cardiovascular health on a continuum across the life course. We discuss key considerations for the transition process for adolescents and young adults with HTN including the major barriers that exist. Finally, we review key immediate health care needs that are particularly important around the time of the transfer of care.

Antihypertensives in Children and Adolescents.

PURPOSE OF REVIEW: To review target organ outcomes and current pharmacologic treatment options for children and adolescents with hypertension. RECENT FINDINGS: There is an increased prevalence of pediatric hypertension. Following the 2017 AAP clinical practice guidelines, there is a growing body of literature illustrating the association between pediatric hypertension and end organ damage, though few studies looking at long-term outcomes. There is also new data to support the use of n-of-1 trials to identify the best antihypertensive therapy for an individual. Pediatric hypertension is increasing in prevalence and is associated with end organ damage. Treatment of hypertensive children has been shown to reverse end organ damage. Due to the lack of large, randomized trials assessing antihypertensive classes against one another, n-of-1 studies may serve as a viable and safe option to optimize patient care.

Nocturnal Hypertension in Children With Chronic Kidney Disease Is Common and Associated With Progression to Kidney Replacement Therapy.

BACKGROUND: Nocturnal hypertension is a risk factor for chronic kidney disease (CKD) progression among adults. In children, effects of nocturnal hypertension on CKD progression is less studied. METHODS: We investigated the relationships between nocturnal, daytime, or sustained hypertension and progression to kidney replacement therapy in children using Cox proportional hazards models. Nocturnal and diurnal hypertension respectively defined as: mean blood pressure >95th percentile and/or load >25% for either systolic or diastolic blood pressure within sleep or wake periods. RESULTS: One thousand five hundred seventy-seven ambulatory blood pressure monitoring studies from 701 CKiD participants were reviewed. Nighttime, daytime, and both types of hypertension were 19%, 7%, and 33%, respectively. Participants with both daytime and nocturnal hypertension had the highest risk of kidney replacement therapy. Among children with CKD, compared with those who were normotensive, those with isolated nocturnal hypertension had a hazard ratio of 1.49 ([CI, 0.97-2.28]; P=0.068) while those with both daytime and nocturnal hypertension had a HR of 2.23 ([CI, 1.60-3.11]; P<0.001) when adjusted for age, race, sex, and baseline proteinuria and glomerular filtration. Estimates for risk were similar among glomerular and nonglomerular participants but not significant in glomerular due to smaller sample size. CONCLUSIONS: The presence of both daytime and nocturnal hypertension is significantly associated with risk of kidney replacement therapy. Our study confirms the utility of ambulatory blood pressure monitoring in children with CKD. Identifying and controlling both daytime and nocturnal hypertension using ambulatory blood pressure monitoring may improve outcomes and delay CKD progression in this population.

Machine Learning-Based Prediction of Masked Hypertension Among Children With Chronic Kidney Disease.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is routinely performed in children with chronic kidney disease to identify masked hypertension, a risk factor for accelerated chronic kidney disease progression. However, ABPM is burdensome, and developing an accurate prediction of masked hypertension may allow using ABPM selectively rather than routinely. METHODS: To create a prediction model for masked hypertension using clinic blood pressure (BP) and other clinical characteristics, we analyzed 809 ABPM studies with nonhypertensive clinic BP among the participants of the Chronic Kidney Disease in Children study. RESULTS: Masked hypertension was identified in 170 (21.0%) observations. We created prediction models for masked hypertension via gradient boosting, random forests, and logistic regression using 109 candidate predictors and evaluated its performance using bootstrap validation. The models showed C statistics from 0.660 (95% CI, 0.595-0.707) to 0.732 (95% CI, 0.695-0.786) and Brier scores from 0.148 (95% CI, 0.141-0.154) to 0.167 (95% CI, 0.152-0.183). Using the possible thresholds identified from this model, we stratified the dataset by clinic systolic/diastolic BP percentiles. The prevalence of masked hypertension was the lowest (4.8%) when clinic systolic/diastolic BP were both <20th percentile, and relatively low (9.0%) with clinic systolic BP<20th and diastolic BP<80th percentiles. Above these thresholds, the prevalence was higher with no discernable pattern. CONCLUSIONS: ABPM could be used selectively in those with low clinic BP, for example, systolic BP<20th and diastolic BP<80th percentiles, although careful assessment is warranted as masked hypertension was not completely absent even in this subgroup. Above these clinic BP levels, routine ABPM remains recommended.

Association of Blood Pressure-Related Increase in Vascular Stiffness on Other Measures of Target Organ Damage in Youth.

BACKGROUND: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)-related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. METHODS: Participants were stratified by systolic BP into low- (systolic BP <75th percentile, n=155), mid- (systolic BP ≥80th and <90th percentile, n=88), and high-risk BP categories (≥90th percentile, n=139), based on age-, sex- and height-specific pediatric BP cut points. Clinic BP, 24-hour ambulatory BP monitoring, anthropometrics, and laboratory data were obtained. Arterial stiffness measures included carotid-femoral pulse wave velocity and aortic stiffness. Left ventricular mass index, left ventricular systolic and diastolic function, and urine albumin/creatinine were collected. ANOVA with Bonferroni correction was used to evaluate differences in cardiovascular risk factors, pulse wave velocity, and cardiac function across groups. General linear models were used to examine factors associated with arterial stiffness and to determine whether arterial stiffness is associated with TOD after accounting for BP. RESULTS: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. CONCLUSIONS: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

BACKGROUND: Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. METHODS: We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. RESULTS: The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). CONCLUSIONS: These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

CCR2 monocytes repair cerebrovascular damage caused by chronic social defeat stress.

Immune surveillance of the brain plays an important role in health and disease. Peripheral leukocytes patrol blood-brain barrier interfaces, and after injury, monocytes cross the cerebrovasculature and follow a pattern of pro- and anti-inflammatory activity leading to tissue repair. We have shown that chronic social defeat (CSD) causes scattered vasculature disruptions. Here, we assessed CCR2+ monocyte trafficking to the vascular injury sites in Ccr2wt/rfp reporter mice both during CSD and one week following CSD cessation. We found that CSD for 14 days induced microhemorrhages where plasma fibrinogen leaked into perivascular spaces, but it did not affect the distribution or density of CCR2rfp+ monocytes in the brain. However, after recovery from CSD, many vascularly adhered CCR2+ cells were detected, and gene expression of the CCR2 chemokine receptor ligands CCL7 and CCL12, but not CCL2, was elevated in endothelial cells. Adhered CCR2+ cells were mostly the non-classical, anti-inflammatory Ly6Clo type, and they phagocytosed fibrinogen in perivascular spaces. In CCR2-deficient Ccr2rfp/rfp mice, fibrinogen levels remained elevated in recovery. Fibrinogen infused intracerebroventricularly induced CCR2+ cells to adhere to the vasculature and phagocytose perivascular fibrinogen in Ccr2wt/rfp but not Ccr2rfp/rfp mice. Depletion of monocytes with clodronate liposomes during CSD recovery prevented fibrinogen clearance and blocked behavioral recovery. We hypothesize that peripheral CCR2+ monocytes are not elevated in the brain on day 14 at the end of CSD and do not contribute to its behavioral effects at that time, but in recovery following cessation of stress, they enter the brain and exert restorative functions mediating vascular repair and normalization of behavior.

Discordances between pediatric and adult thresholds in the diagnosis of hypertension in adolescents with CKD.

BACKGROUND: Adolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults. METHODS: In this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively. RESULTS: Overall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4-5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8-3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure. CONCLUSION: Overall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension.