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.

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.

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.

Social Determinants of Cardiovascular Health in African American Children With CKD: An Analysis of the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: To identify differences in socioeconomic factors (SES) and subclinical cardiovascular disease (CVD) markers by race among Chronic Kidney Disease in Children (CKiD) participants and determine whether differences in CVD markers persist after adjusting for SES. STUDY DESIGN: Analysis of 3,103 visits with repeated measures from 628 children (497 White participants; 131 African American participants) enrolled in the CKiD study. SETTING & PARTICIPANTS: Children with mild-moderate CKD with at least 1 cardiovascular (CV) parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured. EXPOSURE: African American race. OUTCOMES: Ambulatory hypertension, LVMI, triglycerides, high-density lipoprotein cholesterol. ANALYTICAL APPROACH: Due to increased CV risks of glomerular disease, the analysis was stratified by CKD cause. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers. RESULTS: African American children were disproportionately affected by adverse SES. African Americans with nonglomerular CKD had more instances of ambulatory hypertension and higher LVMI but more favorable lipid profiles. After adjustment for SES, age, and sex, the magnitude of differences in these CV markers was attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES. LIMITATIONS: Study design limits causal inference. CONCLUSION: African American children with CKD are disproportionately affected by socioeconomic disadvantages compared with White children. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with nonglomerular CKD have increased LVMI, more ambulatory hypertension, and favorable lipid profile, but attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD had increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.

Prognostic value of ambulatory blood pressure and clinical use of echocardiography to detect left ventricular hypertrophy in children evaluated for primary hypertension.

BACKGROUND: Hypertension (HTN) is common in children and often associated with pathologic progression to end organ damage, specifically left ventricular hypertrophy (LVH). METHODS: The primary goal of this retrospective chart review is to determine if patients with higher blood pressure were more likely to complete echocardiogram (ECHO) and more likely to have LVH, among a pediatric population referred for hypertension evaluation before the 2017 American Academy of Pediatrics (AAP) guidelines. To meet this goal, the number of patients evaluated by ECHO and prevalence of LVH was examined for independent associations with blood pressure and BMI categories by logistic regression. RESULTS: It was found that higher blood pressure was associated with having an ECHO evaluation (p = 0.012). Among patients evaluated by ECHO, one-third had LVH but the presence of LVH was not associated with blood pressure severity or use of anti-hypertensive medication. Instead, BMI was the only factor associated with LVH cardiac remodeling in our population (p = 0.025). CONCLUSIONS: Newly updated AAP practice guidelines recommend evaluation of HTN via ABPM, with ECHO performed only at the initiation of pharmaceutical therapy. It is notable that BMI, the only risk factor of LVH found in this study, is not addressed in the current AAP guidelines for ECHO evaluation among hypertensive children. This study suggests that ECHO evaluation may be warranted in a larger subset of children as is recommended by current European Society of Hypertension pediatric guidelines.

Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015. OBJECTIVES: To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology. MAIN RESULTS: Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone compared to prednisone had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, and infection. Death and malignancy were not reported. Effects of other immunosuppressive regimens (including steroid plus non-immunosuppressive agents or mTOR inhibitors) were inconclusive primarily due to insufficient data from the individual studies in low or very low certainty evidence. The effects of treatments on death, malignancy, reduction in GFR at least of 25% and adverse events were very uncertain. Subgroup analyses to determine the impact of specific patient characteristics such as ethnicity or disease severity on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.

Association of blood pressure variability and neurocognition in children with chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) and hypertension have increased blood pressure variability (BPV), which has been associated with lower neurocognitive test scores in adults. Children with CKD are at risk for decreased neurocognitive function. Our objective was to determine whether children with CKD and increased BPV had worse performance on neurocognitive testing compared with children with CKD and lower BPV. METHODS: This was a cross-sectional and longitudinal analysis of the relation between BPV and neurocognitive test performance in children ≥6 years enrolled in the Chronic Kidney Disease in Children (CKiD) study. Visit-to-visit BPV was assessed by the standard deviation of visit BPs (BPV-SD) and average real variability (ARV). Ambulatory BPV was assessed by SD of wake and sleep periods on 24-h ambulatory BP monitoring. RESULTS: We assessed 650 children with a mean follow-up period of 4.0 years. Children with systolic visit-to-visit BPV in the upper tertile had lower scores on Delis-Kaplan Executive Function System (D-KEFS) Verbal Category Switching than those with BPV in the lower tertile (BPV-SD, 8.3 vs. 9.5, p = 0.006; ARV, 8.5 vs. 9.6, p = 0.02). On multivariate analysis, the association between lower Category Switching score and increased BPV remained significant after controlling for mean BP, demographic characteristics, and disease-related variables [BPV-SD, ß = -0.7, 95 % confidence interval (CI) -1.28 to -0.12; ARV, ß = -0.54, CI -1.05 to -0.02). Ambulatory BPV was not independently associated with any cognitive measure. CONCLUSIONS: Higher systolic visit-to-visit BPV was independently associated with decreased D-KEFS Category Switching scores in children with mild-to-moderate CKD.

Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis world-wide and a cause of end-stage kidney disease (ESKD) in 15% to 20% of patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a review first published in 2003. OBJECTIVES: To determine the benefits and harms of immunosuppression for the treatment of IgAN. SEARCH METHODS: For this review update we searched the Specialised Register to 19 February 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgAN in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data for population characteristics, interventions and outcomes including mortality, infection, hospitalisation, ESKD requiring renal replacement therapy (dialysis or kidney transplantation), doubling of serum creatinine, remission of proteinuria, and end of treatment urinary protein excretion, serum creatinine, and glomerular filtration rate.Estimates of treatment effect and hazards were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included 32 studies comprising 1781 participants. Risk of bias within the included studies was generally high: 22 studies (69%) did not describe the method used to generate the randomisation sequence; 24 (75%) did not describe the methods used to conceal allocation; performance bias was not reported or high in 30 studies (94%); detection bias was unclear in 31 studies (97%); attrition bias was low in 14 studies (44%), unclear in eight (25%) and high in 12 studies (38%); reporting bias was low in 21 studies (67%) and high in 10 studies (31%); and four studies received industry funding or were terminated early (13%).Steroids lowered risks of progression to ESKD (6 studies, 341 participants: RR 0.44, 95% CI 0.25 to 0.80), and doubling of serum creatinine (6 studies, 341 participants: RR 0.45, 95% CI 0.29 to 0.69), lowered urinary protein excretion (6 studies, 263 participants: MD -0.49 g/24 h, 95% CI -0.72 to -0.25); and preserved glomerular filtration rate (4 studies, 138 participants: MD 17.87 mL/min/1.73 m(2), 95% CI 4.93 to 30.82) compared to no treatment or placebo. Combining steroids plus renin-angiotensin-system (RAS) inhibitors lowered the risk of progression to ESKD (2 studies, 160 participants: RR 0.16, 95% CI 0.04 to 0.59) and reduced urinary protein excretion (1 study, 38 participants: MD -0.20 g/24 h, 95% CI -0.26 to -0.14) compared with RAS inhibitors or steroids alone. Cytotoxic agents (azathioprine) plus steroid regimens plus dipyridamole increased remission of proteinuria (1 study, 78 participants: RR 1.24, 95% CI 1.01 to 1.52) compared to steroids alone but had uncertain effects on other outcomes.Mycophenolate mofetil plus RAS inhibitors lowered the risk of progression to ESKD (1 study, 40 participants: RR 0.22, 95% CI 0.05 to 0.90), improved remission of proteinuria (1 study, 40 participants: RR 2.67, 95% CI 1.32 to 5.39) and reduced urinary protein excretion (1 study, 40 participants: MD -1.26 g/24 h, 95% CI -1.46 to -1.06). Effects of other immunosuppressive regimens (including cyclosporin, leflunomide) were inconclusive primarily due to insufficient data from the individual studies. Subgroup analyses to determine the impact of patient characteristics on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: The optimal management of IgAN remains uncertain although corticosteroid therapy may lower the risks of kidney disease progression and need for dialysis or transplantation. Evidence for treatment effects of immunosuppressive agents on mortality, infection, and cancer is generally sparse or low-quality and insufficient to guide clinical practice. Available RCTs are few, small, have high risk of bias - particularly selective reporting - and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible. Larger placebo-controlled studies of corticosteroid therapy or mycophenolate mofetil which are sufficiently powered to evaluate patient-relevant end points including adverse events and that examine the optimal duration of treatment are now required in populations with IgAN with a range of kidney function.

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension.

BACKGROUND: Primary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the comorbid cardiovascular disease risk factors that confound studies in adults. METHODS: Youths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTS: VASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONS: The findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

Low-frequency (<100 kHz), low-intensity (<100 mW/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments.

The purpose of this study was to examine whether low frequency (<100 kHz), low intensity (<100 mW/cm(2), spatial peak temporal peak) ultrasound can be an effective treatment of venous stasis ulcers, which affect 500 000 patients annually costing over $1 billion per year. Twenty subjects were treated with either 20 or 100 kHz ultrasound for between 15 and 45 min per session for a maximum of four treatments. Healing was monitored by changes in wound area. Additionally, two in vitro studies were conducted using fibroblasts exposed to 20 kHz ultrasound to confirm the ultrasound's effects on proliferation and cellular metabolism. Subjects receiving 20 kHz ultrasound for 15 min showed statistically faster (p < 0.03) rate of wound closure. All five of these subjects fully healed by the fourth treatment session. The in vitro results indicated that 20 kHz ultrasound at 100 mW/cm(2) caused an average of 32% increased metabolism (p < 0.05) and 40% increased cell proliferation (p < 0.01) after 24 h when compared to the control, non-treated cells. Although statistically limited, this work supports the notion that low-intensity, low-frequency ultrasound is beneficial for treating venous ulcers.

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.

Prevalence of persistent prehypertension in adolescents.

OBJECTIVE: To measure the prevalence of persistent prehypertension in adolescents. STUDY DESIGN: We collected demographic and anthropometric data and 4 oscillometric blood pressure (BP) measurements on 1020 students. The mean of the second, third, and fourth BP measurements determined each student's BP status per visit, with up to 3 total visits. Final BP status was classified as normal (BP <90th percentile and 120/80 mm Hg at the first visit), variable (BP ≥ 90th percentile or 120/80 mm Hg at the first visit and subsequently normal), abnormal (BP ≥ 90th percentile or 120/80 mm Hg at 3 visits but not hypertensive), or hypertensive (BP ≥ 95th percentile at 3 visits). The abnormal group included those with persistent prehypertension (BP ≥ 90th percentile or 120/80 mm Hg and <95th percentile on 3 visits). Statistical analysis allowed for comparison of groups and identification of characteristics associated with final BP classification. RESULTS: Of 1010 students analyzed, 71.1% were classified as normal, 15.0% as variable, 11.5% as abnormal, and 2.5% as hypertensive. The prevalence of persistent prehypertension was 4.0%. Obesity similarly affected the odds for variable BP (OR, 3.9; 95% CI, 2.5-6.0) and abnormal BP (OR, 3.4; 95% CI, 2.0-5.9), and dramatically increased the odds for hypertension (OR, 38.4; 95% CI, 9.4-156.6). CONCLUSION: Almost 30% of the students had at least one elevated BP measurement significantly influenced by obesity. Treating obesity may be essential to preventing prehypertension and/or hypertension.

Reliability of resting blood pressure measurement and classification using an oscillometric device in children with chronic kidney disease.

OBJECTIVE: To compare the reliability of blood pressure (BP) readings obtained with an oscillometric device with those obtained by auscultation and assess for differences in BP status classification based on the 2 techniques. STUDY DESIGN: Resting BP was measured by auscultation and with an oscillometric device at the same encounter in 235 subjects enrolled in the Chronic Kidney Disease in Children study. Resting auscultatory BP values were averaged and compared with averaged oscillometric readings. BP agreement by the 2 methods was assessed using Bland-Altman plots, and BP status classification agreement was assessed by calculation of kappa statistics. RESULTS: Oscillometric BP readings were higher than auscultatory readings, with a median paired difference of 9 mm Hg for systolic BP (SBP) and 6 mm Hg for diastolic BP (DBP). Correlation for mean SBP was 0.624 and for mean DBP was 0.491. The bias for oscillometric BP measurement was 8.7 mm Hg for SBP (P < .01) and 5.7 mm Hg for DBP (P < .01). BP status classification agreement was 61% for SBP and 63% for DBP, with Kappa values of .31 for SBP and .20 for DBP. CONCLUSIONS: Compared with auscultation, the oscillometric device significantly overestimated both SBP and DBP, leading to frequent misclassification of BP status.

Diffuse near-infrared spectroscopy prediction of healing in diabetic foot ulcers: a human study and cost analysis.

Wound size reduction has been the standard benchmark for determination of efficacy for diabetic ulcer treatments but due to interclinician error and difficulty measuring irregular wound shapes, this method is unreliable with a positive predictive value of less than 60%. Diffuse near-infrared spectroscopy (DNIRS) uses 70-MHz modulated light in the diagnostic window (650-900 nm) noninvasively to quantify levels of oxy- and deoxy-hemoglobin in the wound bed, which when measured over time, can show a trend toward or away from healing based on the changes in oxy-hemoglobin concentration from week to week. In this study, DNIRS was used to monitor 24 human diabetic foot ulcers longitudinally over the course of 20 weekly or biweekly measurement sessions. In just 4 weeks, the DNIRS system has an 82% positive predictive value (sensitivity of 0.9 and specificity of 0.86; p < 0.002). These data indicate that it could be possible to predict healing in 4 weeks using DNIRS, which can provide objective guidance toward the continuation of costly treatments. Discontinuing ineffective treatments after 4 weeks could have potentially saved over $12,600 per patient, based on the treatment regimen of patients in this study.

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.

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.

Nocturnal Dipping and Left Ventricular Mass Index in the Chronic Kidney Disease in Children Cohort.

BACKGROUND AND OBJECTIVES: The physiologic nocturnal BP decline is often blunted in patients with CKD; however, the consequences of BP nondipping in children are largely unknown. Our objective was to determine risk factors for nondipping and to investigate if nondipping is associated with higher left ventricular mass index in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a cross-sectional analysis of ambulatory BP monitoring and echocardiographic data in participants of the Chronic Kidney Disease in Children study. Multivariable linear and spline regression analyses were used to evaluate the relationship of risk factors with dipping and of dipping with left ventricular mass index. RESULTS: Within 552 participants, mean age was 11 (±4) years, mean eGFR was 53 (±20) ml/min per 1.73 m2, and 41% were classified as nondippers. In participants with nonglomerular CKD, female sex and higher sodium intake were significantly associated with less systolic and diastolic dipping (P≤0.05). In those with glomerular CKD, Black race and greater proteinuria were significantly associated with less systolic and diastolic dipping (P≤0.05). Systolic dipping and diastolic dipping were not significantly associated with left ventricular mass index; however, in spline regression plots, diastolic dipping appeared to have a nonlinear relationship with left ventricular mass index. As compared with diastolic dipping of 20%-25%, dipping of <20% was associated with 1.41-g/m2.7-higher left ventricular mass index (95% confidence interval, -0.47 to 3.29), and dipping of >25% was associated with 1.98-g/m2.7-higher left ventricular mass index (95% confidence interval, -0.77 to 4.73), although these relationships did not achieve statistical significance. CONCLUSIONS: Black race, female sex, and greater proteinuria and sodium intake were significantly associated with blunted dipping in children with CKD. We did not find a statistically significant association between dipping and left ventricular mass index. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_12_20_CJN09810721.mp3.

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.

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.

Ambulatory blood pressure status in children: comparing alternate limit sources.

The American Heart Association has included alternate ambulatory blood pressure (ABP) limits for children published by Wühl in 2002. These updated limits employ the same pediatric cohort data as the previous ABP limits published by Soergel in 1997 but differ in analysis technique. The implications of changing ABP limit source on the diagnosis of hypertension has yet to be examined in a large pediatric cohort. We reviewed 741 ABP monitorings performed in children referred to our hypertension clinic between 1991-2007. Hypertension was defined as 24-h mean blood pressure ≥ 95 th percentile or 24-h blood pressure load ≥ 25%, by Soergel and Wühl limits separately. Six hundred seventy-three (91%) children were classified the same by both limit sources. Wühl limits were more likely than Soergel to classify a child as hypertensive (443 vs. 409, respectively). There was an increased classification of prehypertension and decreased white-coat hypertension by the Wühl method, whereas ambulatory and severe hypertension counts remained relatively the same by both limits sources. The use of either limit source will not significantly affect most clinical outcomes but should remain consistent over long-term research projects. Collection of new normative data from a larger, multiethnic population is needed for better measurement of ABP in children.