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.

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.

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.

Kidney Imaging Surveillance in Commercially Insured Patients With Tuberous Sclerosis Complex.

BACKGROUND: Kidney disease has historically been the primary source of early mortality in adults with tuberous sclerosis complex (TSC). Kidney imaging surveillance promotes early detection of lesions requiring intervention. We describe kidney imaging frequency in relationship to patient-level characteristics for commercially insured patients with TSC in the United States. METHODS: This retrospective observational study used 2003 to 2016 enrollment and claims data from a de-identified fully insured commercial health insurer. Patients with TSC less than 65 years were included. The patient-level kidney imaging rate was calculated as the number of kidney imaging procedures divided by length of continuous enrollment. A multiple linear regression model was used to determine the relationship between imaging rate and progression of TSC-associated kidney disease, number of specialists seen, and nephrologist care. RESULTS: At least half of the 70 patients with TSC included in the study were aged 16 years or younger. Over a follow-up period of up to 14 years, the median kidney imaging rate was 0.13 procedures per year with 43% (N = 30) of patients lacking evidence of kidney imaging during the observation period. Imaging frequency increased with progression of TSC-associated kidney disease, more specialists, and nephrologist care (P < 0.05 for all three in regression model). CONCLUSIONS: A substantial percentage of patients with TSC in the United States are at risk for delayed detection of kidney manifestations due to infrequent kidney imaging surveillance. Multispecialty care, including neurologists, may positively affect kidney surveillance rates.

Two different genetic etiologies for tuberous sclerosis complex (TSC) in a single family.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition that involves abnormalities of the skin, hamartomas in the heart, brain, and kidneys, seizures, as well as TSC-associated neuropsychiatric disorders (TAND). About 90%-95% of individuals with TSC will have an identifiable pathogenic variant in either TSC1 or TSC2. We present here two family members with clinical diagnoses of TSC that were later determined to be due to two different genetic etiologies. METHODS: A 2-year-old Caucasian female (Patient 1) was born to non-consanguineous healthy parents and was determined to have a clinical diagnosis of TSC at 2 months old. Her paternal great-uncle (Patient 2) was also known to have a clinical diagnosis of TSC. Sequencing and deletion/duplication analysis for TSC1 and TSC2 were performed on both individuals. RESULTS: Mutation analysis revealed that both Patient 1 and Patient 2 had identifiable pathogenic variants in TSC2. Patient 1 had c.4800_4801delTG (p.Cys1600Trpfs*2), while Patient 2 had c.4470_4471delinsTT (p.Glu1490_Lys1491delinsAsp*). CONCLUSION: To our knowledge, our clinical report is of significance as it is the third kindred to be identified with affected members with two distinct genetic etiologies for TSC. Our case report highlights the importance of incorporating genetic testing into the clinical evaluation for individuals with features suggestive of TSC.

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.

Hypertension in Children and Adolescents.

Hypertension is a growing problem in children and adolescents, with primary hypertension becoming the most common etiology. In addition to demonstrating that high blood pressure in children and young adults is likely to remain elevated into adulthood, this review (1) addresses important aspects of measuring blood pressure in children and adolescents, (2) defines elevated blood pressure and hypertension in this age group, (3) describes the initial evaluation and workup of abnormally high blood pressure, and (4) introduces treatment strategies for youth with sustained hypertension.

Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis-1 with Everolimus: A Phase II, Open-Label, Single-Arm Trial.

BACKGROUND: Cutaneous neurofibromas cause disfigurement and discomfort in individuals with neurofibromatosis type 1 (NF-1). METHODS: The primary objective of this phase II, open-label, single-arm trial was to assess whether orally administered everolimus reduced the surface volume of cutaneous neurofibromas in patients with NF-1. RESULTS: Of 22 patients who took the study drug, 17 completed the trial; 5 patients withdrew due to adverse events. Sixteen patients had photographs of sufficient quality for assessment of the primary outcome. A significant reduction in lesion surface volume, defined as an end of trial volume > 2 standard errors (SE) less than baseline volume, was observed for 4/31 lesions (13%) from 3/16 patients (19%). Additionally, a statistically significant absolute change in average height for paired lesions was observed (p = 0.048). Although not a prespecified outcome measure, a dramatic reduction in the size of 3 large plexiform neurofibromas with a cutaneous component was also noted and documented by measurement of maximum circumference or magnetic resonance imaging-based volumetric analysis. Adverse events were common in this trial, but no serious adverse events occurred. CONCLUSIONS: Although this was a small, exploratory trial that was not powered for significance, the reduction in surface volume observed in this study is noteworthy assuming that the natural course for untreated lesions is to maintain or increase in volume. Future studies are needed with larger study populations that incorporate longer durations of treatment and better standardization of volumetric measurements. Trial Registration ClinicalTrials.gov Identifier: NCT02332902.

Diagnosis, Evaluation, and Management of High Blood Pressure in Children and Adolescents.

Systemic hypertension is a major cause of morbidity and mortality in adulthood. High blood pressure (HBP) and repeated measures of HBP, hypertension (HTN), begin in youth. Knowledge of how best to diagnose, manage, and treat systemic HTN in children and adolescents is important for primary and subspecialty care providers. OBJECTIVES: To provide a technical summary of the methodology used to generate the 2017 "Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents," an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, and Excerpta Medica Database references published between January 2003 and July 2015 followed by an additional search between August 2015 and July 2016. STUDY SELECTION: English-language observational studies and randomized trials. METHODS: Key action statements (KASs) and additional recommendations regarding the diagnosis, management, and treatment of HBP in youth were the product of a detailed systematic review of the literature. A content outline establishing the breadth and depth was followed by the generation of 4 patient, intervention, comparison, outcome, time questions. Key questions addressed: (1) diagnosis of systemic HTN, (2) recommended work-up of systemic HTN, (3) optimal blood pressure (BP) goals, and (4) impact of high BP on indirect markers of cardiovascular disease in youth. Once selected, references were subjected to a 2-person review of the abstract and title followed by a separate 2-person full-text review. Full citation information, population data, findings, benefits and harms of the findings, as well as other key reference information were archived. Selected primary references were then used for KAS generation. Level of evidence (LOE) scoring was assigned for each reference and then in aggregate. Appropriate language was used to generate each KAS based on the LOE and the balance of benefit versus harm of the findings. Topics that could not be researched via the stated approach were (1) definition of HTN in youth, and (2) definition of left ventricular hypertrophy. KASs related to these stated topics were generated via expert opinion. RESULTS: Nearly 15 000 references were identified during an initial literature search. After a deduplication process, 14 382 references were available for title and abstract review, and 1379 underwent full text review. One hundred twenty-four experimental and observational studies published between 2003 and 2016 were selected as primary references for KAS generation, followed by an additional 269 primary references selected between August 2015 and July 2016. The LOE for the majority of references was C. In total, 30 KASs and 27 additional recommendations were generated; 12 were related to the diagnosis of HTN, 13 were related to management and additional diagnostic testing, 3 to treatment goals, and 2 to treatment options. Finally, special additions to the clinical practice guideline included creation of new BP tables based on BP values obtained solely from children with normal weight, creation of a simplified table to enhance screening and recognition of abnormal BP, and a revision of the criteria for diagnosing left ventricular hypertrophy. CONCLUSIONS: An extensive and detailed systematic approach was used to generate evidence-based guidelines for the diagnosis, management, and treatment of youth with systemic HTN.

Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis Complex: The TREATMENT Randomized Clinical Trial.

Importance: Facial angiofibromas occur in approximately 75% of individuals with tuberous sclerosis complex (TSC), causing substantial morbidity and disfigurement. Current therapies are partially effective, uncomfortable, produce scarring, and need repeating to treat recurrence. Objective: To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas. Design, Setting, and Participants: This prospective, multicenter, randomized, double-blind, vehicle-controlled trial with 6 monthly clinic visits enrolled 179 patients with TSC-related facial angiofibromas not treated within 6 months from May 2012 to March 2014 in 9 clinical sites in the United States and 1 in Australia. Interventions: Patients were randomized (1:1:1) to topical formulation containing 0.3 g per 30 g (1%) rapamycin, 0.03 g per 30 g (0.1%) rapamycin, or vehicle alone. Participants applied 1.0 mL to designated areas daily at bedtime. Main Outcomes and Measures: Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses included adverse events (AEs) and serum rapamycin levels. Results: All 179 patients randomized (99 [55.3%] female) comprised the primary analysis population (59 in the 1% rapamycin group, 63 in the 0.1% rapamycin group, and 57 in the vehicle-only group). The mean age was 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromas was observed for both 1% and 0.1% rapamycin relative to the vehicle-only control group, and for 1% vs 0.1% rapamycin, with most of the improvement realized within the first month. At 6 months, AGS mean improvement for 1% rapamycin was 16.7 points compared with 11.0 for 0.1% rapamycin and 2.1 points for vehicle only (P < .001 for 1% and 0.1% vs vehicle only). Compared with baseline, end-of-treatment photos were rated "better" for 81.8% of patients in the 1% rapamycin group, compared with 65.5% for those in the 0.1% rapamycin group and 25.5% for those in the vehicle-only group (P < .001, all 3 pairwise comparisons). Topical rapamycin was generally well-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effects were limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEs were mild, with no drug-related moderate, severe, or serious events. Conclusions and Relevance: Topical rapamycin appears effective and safe for treatment of TSC-related facial angiofibromas. In this trial, the preferred dose was 1% once daily. Future studies are needed to evaluate prophylactic, early, and long-term use of topical rapamycin, durability of response, and combination therapy with oral mammalian target of rapamycin (mTOR) inhibitors. Trial Registration: ClinicalTrials.gov Identifier: NCT01526356.

Varying blood pressure in children: a diagnostic quandary interpreting the Fourth Report.

Fourth Report guidelines on pediatric blood pressure (BP) are not clear when defining hypertension in children as "an average systolic BP and/or diastolic BP ≥ 95th percentile for gender, age, and height on ≥ 3 occasions." We aimed to determine the prevalence of pediatric hypertension in a screening population based on two different guideline interpretations. Prevalence of hypertension among 2094 students at four Houston area schools was calculated based on the summation or sustained model definition from Fourth Report guidelines. Summation hypertension definition required the single average of the BPs recorded across three visits to be elevated. Sustained hypertension definition required BP at each of three visits to be elevated. Hypertension prevalence by the summation method was 7%, whereas sustained prevalence was only 3.3%. Nearly a quarter of students had varying BP and were not classifiable by the sustained method but most would be classified as normal or prehypertensive by the summation method. The prevalence of hypertension among adolescents doubled depending on the interpretation of Fourth Report guidelines. Although methods in research studies can be clearly examined on publication of results, it is unknown which interpretation method is being used in clinical practice.

Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents.

These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.

Treatment of Renal Angiomyolipoma and Other Hamartomas in Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex is an autosomal dominant genetic disease characterized by growth of benign tumors (hamartomas) in multiple organs, especially the kidneys, brain, heart, lungs, and skin. Tuberous sclerosis complex is usually caused by a mutation in either the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 gene, resulting in constitutive activation of mammalian target of rapamycin signaling. Currently, mammalian target of rapamycin inhibitors are recommended in adult patients with tuberous sclerosis complex for the treatment of asymptomatic, growing renal angiomyolipoma that are >3 cm in diameter and pediatric or adult patients with brain lesions (subependymal giant cell astrocytoma) that either are growing or are not amenable to surgical resection. Clinical evidence suggests that systemic administration of a mammalian target of rapamycin inhibitor may provide concurrent improvements in multiple lesions and symptoms of tuberous sclerosis complex. With the major paradigm shift in consensus guidelines toward screening at diagnosis and ongoing monitoring and with the recent availability of an effective oral treatment, it is important that nephrologists have a thorough understanding of our role in the management of patients with tuberous sclerosis complex. Because the various manifestations of tuberous sclerosis complex typically emerge at different periods during patients' lifetimes, patients will need to be followed throughout their lives. Unlike brain and cardiac lesions, renal lesions are more likely to emerge as patients age and can grow at any time. Considerations regarding long-term medication administration for the potential control of multiple tuberous sclerosis complex manifestations will need to be addressed; these include the most appropriate starting dose, appropriate doses for tumor shrinkage versus prevention of regrowth, and management of adverse events. Best practices and potential obstacles for nephrologists treating patients with tuberous sclerosis complex who have multiple manifestations are considered.

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.

Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin.

BACKGROUND AND OBJECTIVES: Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas. PATIENTS AND METHODS: The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas. RESULTS: Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas. CONCLUSION: The application of low-dose topical rapamycin (0.003-0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01031901.

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.