Faculty Bibliography

AIMS/OBJECTIVE:We sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes. METHODS:in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR. RESULTS:Estimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index. CONCLUSIONS:Over the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.

OBJECTIVE:Diabetes surveillance often requires manual medical chart reviews to confirm status and type. This project aimed to create an electronic health record (EHR)-based procedure for improving surveillance efficiency through automation of case identification. RESEARCH DESIGN AND METHODS/METHODS:= 8,682) were identified from EHRs at three children's hospitals participating in the SEARCH for Diabetes in Youth Study. True diabetes status/type was determined by manual chart reviews. Multinomial regression was compared with an ICD-10 rule-based algorithm in the ability to correctly identify diabetes status and type. Subsequently, the investigators evaluated a scenario of combining the rule-based algorithm with targeted chart reviews where the algorithm performed poorly. RESULTS:, and PPV for type 2 diabetes using the combined method were ≥0.91. CONCLUSIONS:An ICD-10 algorithm combined with targeted chart reviews accurately identified diabetes status/type and could be an attractive option for diabetes surveillance in youth.

Introduction/UNASSIGNED:and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods/UNASSIGNED: < 0.001). Results/UNASSIGNED:score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion/UNASSIGNED:score predict age of ESKD.

[This corrects the article DOI: 10.1016/j.conctc.2018.05.002.].

BACKGROUND:Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction. METHODS:Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction. RESULTS:After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction. CONCLUSION/CONCLUSIONS:Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy.

AIMS/OBJECTIVE:To evaluate cardiovascular risk factors and heart rate variability (HRV) in young adults with type 2 diabetes and arterial stiffness and to explore the relationship between HRV and arterial stiffness. METHODS:We studied 185 young adults with youth-onset T2D enrolled in the SEARCH for Diabetes in Youth Study. Cardiovascular risk factors and HRV were compared between individuals with and without type 2 diabetes and arterial stiffness (defined as a pulse wave velocity greater than the 90th percentile of healthy controls, >6.767 m/s). Semiparametric regression evaluated the independent relationship between HRV and PWV. RESULTS:Participants with T2D and arterial stiffness were more likely to be older, non-Hispanic Black, have higher systolic and diastolic blood pressure, greater adiposity and obesity-related dyslipidemia (higher triglycerides and lower HDLC). Participants with T2D and arterial stiffness also had lower overall HRV (lower SDNN) with parasympathetic loss (lower RMSSD and PNN50), p < 0.05. Lower HRV tended to be but was not significantly associated with arterial stiffness after adjustment for age, race/ethnicity, sex and cardiovascular risk factors (beta coefficient = -1.11, p = 0.08). CONCLUSIONS:Youth with T2D and arterial stiffness have a worse cardiovascular risk profile, specifically risk factors related to the metabolic syndrome and lower HRV.

Introduction/UNASSIGNED:-nephropathy. Methods/UNASSIGNED:A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed. Results/UNASSIGNED:G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2. Conclusion/UNASSIGNED:-nephropathy.

BACKGROUND:"Energy drinks" are heavily marketed to the general public, across the age spectrum. The efficacy of decaffeinated energy drinks in enhancing subjective feelings of energy (s-energy) is controversial. OBJECTIVE:The authors sought to test the efficacy of the caffeine-free version of a popular energy drink compared with a placebo drink. METHODS:This study was a randomized, double-blind, placebo-controlled, crossover trial in 223 healthy men and women aged 18-70 y with intention-to-treat and completers analysis. Participants were randomly assigned to consumption of either the decaffeinated energy drink or a placebo drink on testing day 1, and the other drink a week later. A battery of computer-based mood and cognitive tests to assess s-energy was conducted at baseline and at 0.5, 2.5, and 5 h post-ingestion. The main outcome measures were 1) mood, which was assessed by using a General Status Check Scale and the Profile of Mood States 2nd edition brief form, and 2) cognitive measures, including the N-back task (reaction time and accuracy), Reaction Time test, Flanker task (distraction avoidance), and Rapid Visual Information Processing test. RESULTS:No statistically significant or meaningful benefits were observed for any outcome measure, including mood and cognitive measures. Analyses of mean differences, slopes, and median differences were consistent. CONCLUSIONS:No differences were detected across a range of mood/cognitive/behavioral/s-energy-level tests after consumption of the energy drink compared with a placebo drink in this diverse sample of adults. Thus, we found strong evidence that the energy drink is not efficacious in enhancing s-energy levels, nor any related cognitive or behavioral variables measured. In light of federal regulations, these findings suggest that labeling and marketing of some products which claim to provide these benefits may be unsubstantiated. This trial was registered at www.clinicaltrials.gov as NCT02727920.

Introduction/UNASSIGNED:genotypes. Methods/UNASSIGNED:APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results/UNASSIGNED:The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion/UNASSIGNED:genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (p=1.6x10^-8 -2.2x10^-8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; p=2x10^-9 -3.7x10^-8 ) and plasmacytoma variant translocation 1 (PVT1) genes (p=4.0x10^-8 -7x10^-8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (p=2x10^-9 -5x10^-8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.