Faculty Bibliography

In people of African ancestry, apolipoprotein L1 gene (APOL1) variants have been identified as causing increased risk of progressive chronic kidney disease (CKD). In April of 2024, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on APOL1 Kidney Disease in Accra, Ghana. The goals of the conference were to review and discuss current evidence and controversies on APOL1 kidney disease, including naming, epidemiology, pathophysiology, APOL1 testing, treatment, and future research needs. Participants considered various terminologies for diseases related to APOL1 risk variants (such as APOL1-mediated or -induced kidney disease) and had highest support for using APOL1 kidney disease to describe kidney pathologies associated with the APOL1 G1 and G2 risk variants. Clinically, the term APOL1 kidney disease can be used on its own or as an overall category of kidney disease, with further specification added as needed (for example, APOL1 kidney disease, focal segmental glomerulosclerosis). Given that there currently are no established treatments for APOL1 kidney disease, and APOL1 genotype results are not by themselves actionable, there is insufficient evidence to guide recommendations for APOL1 population screening or routine testing. However, genotyping can be an important clinical consideration for individuals to inform risk stratification, frequency of follow-up, living kidney donation, as well as clinical trial eligibility. Key areas of need and strategies for future research were delineated and are reported here.

To date, the primary focus of chronic kidney disease (CKD) care has been on managing disease progression, complications, and kidney failure. In contrast, maintaining kidney health and preventing CKD have received limited attention, despite their potential to save millions of lives, reduce health care costs, and lessen environmental burdens. The cardiovascular-kidney-metabolic (CKM) concept frames CKD as part of a complex, high-risk syndrome requiring global risk assessment and multifactorial intervention. CKD incidence along with CKM risk factors may be reduced by a healthy diet, physical activity, and a supportive environment. However, risk for CKD does extend beyond the cardiovascular-metabolic component, and residual risk persists despite healthy lifestyles and treatment of risk factors. Post hoc analyses of clinical trials suggest pharmacological interventions, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, may help to prevent or regress CKD in individuals with type 2 diabetes or obesity. Clinical trials are needed to validate these findings in broader high-risk populations. Personalized strategies to improve kidney health should include CKD risk prediction via targeted testing, genetic or biomarker assessments, shared decision-making, cost considerations, selection of therapeutics, and the potential for adverse effects. The overall goals of CKD prevention should prioritize a lifespan approach to risk evaluation along with safe, efficacious, and accessible interventions to maintain kidney health.

Targeted therapies and immunotherapy have improved treatment outcomes for many melanoma patients. However, patients whose melanomas harbor driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene often lack effective targeted treatment options when their tumors do not respond to immunotherapy. In this study, we utilized patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could inform the development of therapies for patients with NF1 mutant melanoma. Differential gene expression analysis revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, where it hyper-activates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth. In contrast, genetic or pharmacological inhibition of EGFR hindered cell proliferation and survival and suppressed tumor growth in patient-derived NF1 mutant melanoma models but not in NF1 wild-type models. These results reveal a connection between NF1 loss and increased EGFR expression that is critical for the survival and growth of NF1 mutant melanoma cells in patient-derived culture and xenograft models, irrespective of their BRAF and NRAS mutation status.

Despite recent advances, the regulation of anticancer and antimicrobial bioactive compound (AABC) production by leukocytes remains poorly understood. Here, we demonstrate that inactivation of the DNA- and RNA-based Teazeled receptors of the Universal Receptive System in human leukocytes generated so called "Leukocyte-Tells," which showed enhanced AABC production. Comprehensive analysis of the AABCs produced by Leukocyte-Tells based on LC/MS identified 707 unique or differentially produced peptide or nonpeptide metabolites. Functional testing demonstrated that many of these metabolites exhibited increased antibacterial, antifungal, and anticancer activities. The AABCs produced by the Leukocyte-Tells were effective against different multidrug-resistant clinical isolates of fungi and gram-positive and gram-negative bacteria (including their biofilms), as well as various cancer cell lines, with >100,000-fold activity than AABCs derived from control leukocytes. Notably, the AABCs produced by the Leukocyte-Tells exhibited greater stability under adverse environmental conditions. Our findings highlight the important role of the Universal Receptive System in regulating AABC production through a process named here as cell genome-memory management, offering new insights into immune functions and suggesting potential therapeutic applications.

OBJECTIVE:The objective of this study is to examine real-world dose titration patterns of semaglutide for weight management (Wegovy, Novo Nordisk A/S) in US adults and identify characteristics associated with early discontinuation. METHODS:We identified 15,811 commercially insured adults who started semaglutide for weight management (administrated through single-dose prefilled pens) between June 2021 and December 2023. We depicted dose-titration patterns over 5 months and identified factors associated with discontinuation using multivariable Cox regression. Sensitivity analyses examined patterns after supply shortage resolution (after October 2023). RESULTS:Most semaglutide users deviated from the recommended monthly dose-escalation schedule within the first 5 months. By the fifth month, nearly one-half (46%) had discontinued the treatment, with similar rates (48%) among those initiating after supply stabilization. Discontinuation was strongly associated with copayment amount, with rates increased from 41% in the lowest quintile ($1-$54 per month) to 51% in the highest quintile ($161-$1460 per month). Higher discontinuation rates were also associated with lower household income and education level. CONCLUSIONS:The deviations from the recommended dose-escalation schedule and high discontinuation rate among real-world semaglutide users indicate important challenges in the delivery of evidence-based care. Policy interventions that reduce financial barriers to the persistence of semaglutide are needed.

AIMS/OBJECTIVE:To characterize changes in continuous glucose monitoring (CGM)-derived time in tight range (TIR) measures in individuals with prediabetes or non-insulin-treated type 2 diabetes undergoing dietary weight loss intervention and to quantify the association between weight loss and TIR improvement. METHODS:) were analysed. The association between weight change and TIR change adjusted for demographic and clinical covariates was computed using linear regression. RESULTS:. There were no associations between weight loss and change in any overnight TIR measure. CONCLUSION/CONCLUSIONS:in individuals with prediabetes and non-insulin-treated type 2 diabetes undergoing dietary intervention. The daytime time in tight range measures can complement traditional markers like HbA1c, offering a more comprehensive view of glycaemic variations during dietary weight loss programmes for individuals with prediabetes and type 2 diabetes not on insulin.

RATIONALE & OBJECTIVE/OBJECTIVE:Despite national efforts, the uptake of home dialysis (peritoneal dialysis or home hemodialysis) remains low. Characteristics of the built environment may differentially impact home dialysis use. STUDY DESIGN/METHODS:Retrospective cohort study (2010-2019). SETTING & PARTICIPANTS/METHODS:1,103,695 adults (aged≥18 years) initiating dialysis in the US Renal Data System. EXPOSURE/METHODS:We examined 3 built environment domains based on residential ZIP code: (1) medically underserved areas (MUAs), defined as neighborhoods with limited primary care access; (2) distance to the nearest dialysis facility; and (3) distribution of housing characteristics (structure and overcrowding). OUTCOME/RESULTS:Uptake of home dialysis modalities at dialysis initiation. ANALYTICAL APPROACH/METHODS:We quantified associations between built environment characteristics and home dialysis initiation using multilevel logistic regression stratified by urbanicity type (urban, suburban, small-town, and rural). RESULTS:Among adults initiating dialysis, 40.8% lived in MUAs. Across ZIP codes, the mean percentage of overcrowded housing was 4.2% (SD, 4.7%), and the percentage of detached housing was 61.1% (SD, 21.1%); mean distance to the nearest dialysis facility was 5.5km (SD, 9.1km). Living in MUAs was associated with reduced home dialysis use only in urban (OR, 0.94; 95% CI, 0.91-0.96) and suburban (OR, 0.92; 95% CI, 0.89-0.94) areas. Similarly, housing overcrowding was associated with decreased home dialysis use only in urban (OR, 0.88; 95% CI, 0.86-0.89) and suburban (OR, 0.91; 95% CI, 0.90-0.93) areas. Longer distance to a dialysis facility was the most salient neighborhood factor associated with increased home dialysis use in small towns (OR, 1.14; 95% CI, 1.12-1.16) and rural areas (OR, 1.17; 95% CI, 1.15-1.19). LIMITATIONS/CONCLUSIONS:Housing characteristics were measured at the ZIP code level. CONCLUSIONS:Built environment characteristics associated with home dialysis uptake vary by urbanicity. Policies should address built environment barriers that are specific to urbanicity level. For example, increasing the frequency of dialysate delivery schedules could address housing space constraints in urban and suburban areas, and promoting home dialysis might be more effective for patients living far from dialysis centers in small-town and rural areas.

AIMS/OBJECTIVE:To characterize trends in obesity and prescriptions for glucagon-like peptide-1 receptor agonists (GLP-1RAs) across body mass index (BMI) categories among US youth and adults with type 1 diabetes (T1D) from 2008 to 2023. MATERIALS AND METHODS/METHODS:Patients with T1D were identified using a validated algorithm using de-identified electronic health record (EHRs) data from 33 US health systems. BMI categories were based on age- and sex-specific percentiles for youth (2-19 years) and World Health Organization cut points for adults (≥20 years). Trends in obesity and GLP1-RA prescriptions were characterized by BMI categories among youth and adults with T1D from 2008-2011 to 2020-2023. RESULTS:From 2008-2011 to 2020-2023, the prevalence of obesity among youth with T1D increased from 18.1% (95% confidence interval [CI], 17.3%-18.9%) to 26.0% (25.2%-26.8%) (p-for-trend < 0.001). Among adults with T1D, the prevalence of obesity rose from 30.5% (30.0%-31.0%) in 2008-2011 to 38.1% (37.8%-38.5%) in 2020-2023 (p-for-trend < 0.001). Obesity was highest in Black and Hispanic youth and adults, and racial and ethnic disparities persisted over time. Over the last 15-year period, GLP-1RA prescriptions significantly increased across all BMI categories in a dose-response manner among both youth and adults with T1D (all p-for-trend < 0.001). CONCLUSIONS:Over the last 15-year period, obesity has reached epidemic levels in US youth and adults with T1D, with significant disparities among racial and ethnic minoritized populations. These findings, coupled with the increase in GLP-1RA prescriptions, underscore the urgent need for data on GLP-1RAs' safety and effectiveness and guidance for obesity management in T1D.

OBJECTIVE:To estimate the prevalence of polypharmacy (concomitant use of ≥5 medications), hyperpolypharmacy (≥10 medications), and potentially inappropriate medication (PIM) use among older adults according to dementia and frailty status. PATIENTS AND METHODS/METHODS:Cross-sectional data (2016-2017) from 3912 participants aged 71 to 94 years (mean ± SD, 79.6±4.8 years; 59.2% female; 24.5% Black race) from the community-based Atherosclerosis Risk in Communities (ARIC) study were used. Dementia and mild cognitive impairment status was based on comprehensive neurocognitive assessment, informant interviews, and adjudication by an expert panel. Participants were classified as frail, prefrail, or robust according to the Fried frailty phenotype definition. Medication containers were brought to the clinic. The PIMs were defined using a modified version of the Beers Criteria. RESULTS:Polypharmacy, hyperpolypharmacy, and PIM use were prevalent in 67.1%, 18.8%, and 23.9% of participants, respectively, and 7.9% were classified as having dementia and 8.0% as frail. The demographic-adjusted relative risk ratio (95% CI) for participants with dementia vs normal cognition was 1.79 (1.27 to 2.51) for hyperpolypharmacy, and the odds ratio (95% CI) for PIM use was 1.58 (1.21 to 2.06). The relative risk ratios (95% CIs) for hyperpolypharmacy were 8.35 (5.57 to 12.54) for frail and 2.70 (2.14 to 3.41) for prefrail compared with robust. CONCLUSION/CONCLUSIONS:Polypharmacy, hyperpolypharmacy, and PIM use were common in this community-based sample of adults approximately 80 years old. These patterns of use were even more common among participants with dementia and frailty, who are at elevated risk for adverse outcomes.