Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates

AbstractBackgroundPoor nutrition during development programs kidney function. No studies on postnatal consequences of decreased perinatal nutrition exist in nonhuman primates (NHP) for translation to human renal disease. Our baboon model of moderate maternal nutrient restriction (MNR) produces intrauterine growth restricted (IUGR) and programs renal fetal phenotype. We hypothesized that the IUGR phenotype persists postnatally, influencing responses to a high-fat, high-carbohydrate, high-salt (HFCS) diet.MethodsPregnant baboons ate chow (Control; CON) or 70% of control intake (MNR) from 0.16 gestation through lactation. MNR offspring were IUGR at birth. At weaning, all offspring (CON and IUGR females and males, n=3/group) ate chow. At ~4.5 years of age, blood, urine, and kidney biopsies were collected before and after a 7-week HFCS diet challenge. Kidney function, unbiased kidney gene expression, and untargeted urine metabolomics were evaluated.ResultsIUGR female and male kidney transcriptome and urine metabolome differed from CON at 3.5 years, prior to HFCS. After the challenge, we observed sex-specific and fetal exposure-specific responses in urine creatinine, urine metabolites, and renal signaling pathways.ConclusionsWe previously showed mTOR signaling dysregulation in IUGR fetal kidneys. Before HFCS, gene expression analysis indicated that dysregulation persists postnatally in IUGR females. IUGR male offspring response to HFCS showed uncoordinated signaling pathway responses suggestive of proximal tubule injury. To our knowledge, this is the first study comparing CON and IUGR postnatal juvenile NHP and the impact of fetal and postnatal life caloric mismatch. Perinatal history needs to be taken into account when assessing renal disease risk.

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Abstract P302: Longitudinal Evaluation of Impact and Results of the Mississippi Kidney Foundation’s Renal Evaluation and Assessment Program (REAP)

Circulation ◽

10.1161/circ.129.suppl_1.p302 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Laura S Latham ◽

Adam S Woodson ◽

Deborah S Minor ◽

Lynda M Richards ◽

Gail G Sweat ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Renal Disease ◽

Patient Care ◽

Kidney Function ◽

Rural Areas ◽

Disease Risk ◽

Elevated Blood ◽

Reduced Kidney Function ◽

The Impact

Introduction: Health fair-type screenings are one of the most recognizable forms of community-based health promotion. Though these screenings offer benefits in theory, little evidence supports their value. Through REAP, Mississippi Kidney Foundation routinely provides screenings for cardiovascular and renal disease risk factors. At each screening, participants obtain blood pressure, height, weight, laboratory assessments (metabolic/renal blood chemistries, complete blood count, total cholesterol, urinalysis) and complete a questionnaire regarding risk factors and disease history. Participants also receive written information about values/goals and consultation with a healthcare provider. Without a systematic evaluation, the overall value of this program is unknown. The purpose of this study was to review the impact and results of REAP and identify any changes that could improve outreach and patient care. Methods: We reviewed demographics and prevalence of cardiovascular and renal disease risk factors among participants over the previous 4 years (2010-2013). Screening sites were classified as urban or rural, according to census data. Risk factors were defined as elevated blood pressure (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg), cholesterol (total > 200 mg/dL), or blood glucose (fasting ≥ 100 mg/dL); reduced kidney function (elevated BUN/Cr and/or eGFR < 60 ml/min); and proteinuria (≥ 30 mg/dL). Results: Over the review period, 57 screenings were performed at 34 sites, 15 classified as rural. Of the 5,545 participants, 4,299 were at urban and 1,246 at rural sites. Overall, 1,760 (32%) had elevated blood pressure (36% vs 31%, rural vs urban, respectively), 2,013 (36%, 40% vs 35%) elevated cholesterol and 1,046 (19%, 23% vs 18%) elevated glucose. Reduced kidney function was identified in 762 (14%, 15% vs 13%) participants, while 1,423 (26%, 29% vs 25%) had proteinuria. Among those reporting ethnicity (n=1,948) and gender (n=3,164), 614 (32%) were Caucasian, 1,290 (66%) African-American, and 2,270 (72%) female. Conclusions: Through this review, we determined that though REAP appears to target at risk populations, further efforts are needed to improve participation of males and those in rural areas. Elevated risk factors were more prevalent in rural areas; however, this may reflect differences in treatment rates, not absolute values. To better assess the impact of REAP, define risk factors, and influence patient care, we identified that more rigorous tracking, review of disease and treatment history, and further assessments are needed (i.e. full lipid panel). A graded system targeting patient follow-up is necessary, particularly among those at greatest risk. Based on these findings, these changes will be implemented, along with a post-screening evaluation of participants’ perceived benefits and result utilization.

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POS1121 DEMOGRAPHICS, COMORBIDITIES, AND RENAL FUNCTION OF UNCONTROLLED GOUT PATIENTS WHO RECEIVED PEGLOTICASE: FINDING FROM A LARGE US CLAIMS DATABASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.95 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 839.2-840

Author(s):

C. Vesel ◽

A. Morton ◽

M. Francis-Sedlak ◽

B. Lamoreaux

Keyword(s):

Kidney Function ◽

Real World ◽

Randomized Clinical Trials ◽

Small Subset ◽

Phase 3 ◽

Claims Database ◽

Medical Diagnoses ◽

Ckd Stage ◽

Before And After ◽

The Impact

Background:NHANES data indicate that approximately 9.2 million Americans have gout,1 with a small subset having uncontrolled disease.2 Pegloticase is a PEGylated recombinant uricase enzyme indicated for treating uncontrolled gout that markedly reduces serum uric acid levels (sUA)3 and resolves tophi in treatment responders.4 Despite pegloticase availability in the US for many years, real world demographics of pegloticase users in the treatment of uncontrolled gout have not been previously reported in a population-based cohort.Objectives:This study utilized a large US claims database to examine demographics and co-morbidities of uncontrolled gout patients treated with pegloticase. Kidney function before and after pegloticase treatment and concomitant therapy with immunomodulators were also examined.Methods:The TriNetX Diamond database includes de-identified data from 4.3 million US patients with gout (as of September 2019), including demographics, medical diagnoses, laboratory values, procedures (e.g. infusions, surgeries), and pharmacy data. Patients who had received ≥1 pegloticase infusion were included in these analyses. The number of infusions was evaluated for a subgroup of patients who were in the database ≥3 months before and ≥2 years after the first pegloticase infusion (i.e. first infusion prior to September 2017) to ensure only complete courses of therapy were captured. In this subpopulation, kidney function before and after pegloticase therapy was examined, along with the presence of immunomodulation prescriptions (methotrexate, mycophenolate mofetil, azathioprine, leflunomide) within 60 days prior to and 14 days after the first pegloticase infusion.Results:1494 patients treated with pegloticase were identified. Patients were 63.1 ± 14.0 years of age (range: 23–91), mostly male (82%), and white (76%). Mean sUA prior to pegloticase was 8.7 ± 2.4 mg/dL (n=50), indicating uncontrolled gout in the identified population. The most commonly reported comorbidities were chronic kidney disease (CKD, 48%), essential hypertension (71%), type 2 diabetes (39%), and cardiovascular disease (38%), similar to pegloticase pivotal Phase 3 trial populations. In patients with pre-therapy kidney function measures (n=134), pre-treatment eGFR averaged 61.2 ± 25.7 ml/min/1.73 m2, with 44% having Stage 3-5 CKD. In patients with complete therapy course capture and pre- and post-therapy eGFR measures (n=48), kidney function remained stable (change in eGFR: -2.9 ± 18.2 ml/min/1.73 m2) and CKD stage remained the same or improved in 81% of patients. In 791 patients with complete treatment course capture, patients had received 8.7 ± 13.8 infusions (median: 3, IQR: 2-10). Of these, 189 (24%) patients received only 1 pegloticase infusion and 173 (22%) received ≥12 infusions. As the data cut-off for this analysis pre-dated emerging data on the use of immunomodulation as co-therapy, only 19 of 791 (2%) patients received immunomodulation co-therapy with pegloticase.Conclusion:This relatively large group of patients with uncontrolled gout treated with pegloticase had similar patient characteristics of those studied in the phase 3 randomized clinical trials. Patients with uncontrolled gout are significantly burdened with systemic co-morbid diseases. The majority of patients had stable or improved kidney function following pegloticase treatment. As these results reflect patients initiating treatment prior to 2018, before co-treatment with immunomodulation was introduced, this cohort only included a small percentage of patients who were co-treated with an immunomodulator. Future studies using more current datasets are needed to evaluate real world outcomes in patients treated with pegloticase/immunomodulator co-therapy and to evaluate the impact of systemic co-morbid diseases.References:[1]Chen-Xu M, et al. Arthritis Rheumatol 2019 71:991-999.[2]Fels E, Sundy JS. Curr Opin Rheumatol 2008;20:198-202.[3]Sundy J, et al. JAMA 2011;306:711-720.[4]Mandell BF, et al. Arthritis Res Ther 2018;20:286.Disclosure of Interests:Claudia Vesel Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Allan Morton Speakers bureau: Sanofi, Amgen, and Horizon, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

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Evaluation of a Cardiovascular Health Program for Participants with Mental Retardation and Normal Learners

Health Education & Behavior ◽

10.1177/1090198103259162 ◽

2004 ◽

Vol 31 (1) ◽

pp. 77-87 ◽

Cited By ~ 52

Author(s):

Gary Ewing ◽

Suzanne McDermott ◽

Marlo Thomas-Koger ◽

Wendy Whitner ◽

Kristen Pierce

Keyword(s):

Mental Retardation ◽

Stress Reduction ◽

Cardiovascular Health ◽

Vegetable Intake ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Self Report ◽

Before And After ◽

The Impact ◽

Individuals With Mental Retardation

An evaluation was conducted to compare the impact of an 8-week cardiovascular disease risk reduction group teaching program for 92 individuals with mental retardation (MR; IQ less than 70) and 97 normal learners. The curriculum emphasized exercise, nutritional choices, and stress reduction. Body Mass Index (BMI; weight in kilograms, divided by height in meters, squared), knowledge of healthy eating choices, self-report of fruit and vegetable intake, and exercise were measured before and after the intervention. The mean BMI decreased by .89 for normal learners and not at all for the group with MR. However, BMI decreased by at least .75 units (or approximately 5 pounds) for 18.5% of individuals with MR and 44.3% of normal learners.

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The impact of rare variation on gene expression across tissues

10.1101/074443 ◽

2016 ◽

Cited By ~ 10

Author(s):

Xin Li ◽

Yungil Kim ◽

Emily K. Tsang ◽

Joe R. Davis ◽

Farhan N. Damani ◽

...

Keyword(s):

Gene Expression ◽

Rare Variants ◽

Disease Risk ◽

Whole Genome Sequencing Data ◽

Personal Genome ◽

Sequencing Data ◽

Potential Health ◽

Rare Variation ◽

Functional Variants ◽

The Impact

AbstractRare genetic variants are abundant in humans yet their functional effects are often unknown and challenging to predict. The Genotype-Tissue Expression (GTEx) project provides a unique opportunity to identify the functional impact of rare variants through combined analyses of whole genomes and multi-tissue RNA-sequencing data. Here, we identify gene expression outliers, or individuals with extreme expression levels, across 44 human tissues, and characterize the contribution of rare variation to these large changes in expression. We find 58% of underexpression and 28% of overexpression outliers have underlying rare variants compared with 9% of non-outliers. Large expression effects are enriched for proximal loss-of-function, splicing, and structural variants, particularly variants near the TSS and at evolutionarily conserved sites. Known disease genes have expression outliers, underscoring that rare variants can contribute to genetic disease risk. To prioritize functional rare regulatory variants, we develop RIVER, a Bayesian approach that integrates RNA and whole genome sequencing data from the same individual. RIVER predicts functional variants significantly better than models using genomic annotations alone, and is an extensible tool for personal genome interpretation. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues with potential health consequences, and provide an integrative method for interpreting rare variants in individual genomes.

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130 Early Developmental Exposure to Stress and Programming of Lifelong Gut and Immune Function

Journal of Animal Science ◽

10.1093/jas/skab235.125 ◽

2021 ◽

Vol 99 (Supplement_3) ◽

pp. 69-69

Author(s):

Adam J Moeser

Keyword(s):

Life Stress ◽

Disease Risk ◽

Early Life Stress ◽

Later Life ◽

Developmental Programming ◽

Postnatal Life ◽

Critical Periods ◽

Organ Systems ◽

High Level ◽

The Impact

Abstract Prenatal and early postnatal life represents critical periods of development across species for many organ systems including immune, nervous, reproductive, and gastrointestinal systems. A high level of plasticity exists during these periods, and thus maternal and environmental cues including stress, immune stimulation, and nutrition, can alter the normal developmental programming of the fetus and neonate and impact the trajectory for disease risk and productivity across the lifespan. This presentation will focus on the impact of and biological mechanisms by which prenatal and early postnatal stressors, including psychological immune and nutritional stressors, alter the normal developmental programming of the immune, gastrointestinal, and neuroendocrine stress axes in the offspring and how this may link to increased disease risk and reduced productivity across the lifespan in animals and humans. Further, specifically how host factors such as biological sex interact with early life stress to shape gut and systemic neuroimmune development and later life disease risk will be discussed.

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Impact of maternal undernutrition on the hypothalamic–pituitary–adrenal axis responsiveness in sheep at different ages postnatal

Journal of Endocrinology ◽

10.1677/joe-06-0172 ◽

2007 ◽

Vol 192 (3) ◽

pp. 495-503 ◽

Cited By ~ 53

Author(s):

S E Chadio ◽

B Kotsampasi ◽

G Papadomichelakis ◽

S Deligeorgis ◽

D Kalogiannis ◽

...

Keyword(s):

Hpa Axis ◽

Disease Risk ◽

Area Under The Curve ◽

Postnatal Life ◽

Blood Samples ◽

Hypothalamic Pituitary Adrenal ◽

Maternal Undernutrition ◽

Different Ages ◽

Cortisol Levels ◽

The Impact

Epidemiological and experimental data support the hypothesis of ‘fetal programming’, which proposes that alterations in fetal nutrition and endocrine status lead to permanent adaptations in fetal homeostatic mechanisms, producing long-term changes in physiology and determine susceptibility to later disease. Altered hypothalamic–pituitary–adrenal (HPA) axis function has been proposed to play an important role in programming of disease risk. The aim of the present study was to examine the effects of maternal nutrient restriction imposed during different periods of gestation on the HPA axis function in sheep, at different ages postnatal. Pregnant ewes were fed a 50% nutrient-restricted diet from days 0–30 (group R1, n = 7), or from days 31–100 of gestation (group R2, n = 7) or a control 100% diet throughout pregnancy, (Control, n = 8). Blood samples were collected at 10-day intervals from day 40 of gestation to term. Lambs were born naturally and fed to appetite throughout the study period. At 2, 5.5, and 10 months of age lambs were given an i.v. injection of corticotrophin-releasing hormone (CRH) and blood samples were collected at −15, 0, 15, 30, 60, 120, and 180 min postinjection. Maternal cortisol levels were significantly higher (P < 0.05) in group R1 compared with the other two groups, whereas maternal insulin levels were lower (P < 0.05) in group R2 compared with control. Birth weight of lambs was not affected by the maternal nutritional manipulation. The area under the curve for ACTH and cortisol response to CRH challenge was greater (P < 0.05) in lambs of group R1 at two months of age, whereas no difference was detected at the ages of 5.5 and 10 months. However, significantly higher (P < 0.01) basal cortisol levels were observed in lambs of R1 group at 5.5 months of age. There was no interaction between treatment and sex for both pituitary and adrenal responses to the challenge. A significant sex effect was evident with females responding with higher ACTH and cortisol levels at the age of 5.5 months (P < 0.01, P < 0.001 respectively) and with higher cortisol levels (P < 0.01) at 10 months of age than males. It is concluded that the HPA axis is programmable by altered nutrition in utero. The sensitivity of the axis to exogenous stimulation is enhanced during early postnatal life and attenuated with age, suggesting a role for the postnatal influences in resetting of the HPA axis and emphasizing the importance of identifying the impact of maternal undernutrition at several time points after birth.

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Transient Elastography in End-Stage Renal Disease Patients on Hemodialysis: The Effect of Net Fluid Withdrawal

Blood Purification ◽

10.1159/000439582 ◽

2015 ◽

Vol 40 (3) ◽

pp. 256-259 ◽

Cited By ~ 5

Author(s):

Narongrit Khunpakdee ◽

Kullapong Jayanama ◽

Piyaporn Kaewdoung ◽

Kwannapa Promson ◽

Sasivimol Rattanasiri ◽

...

Keyword(s):

Renal Disease ◽

End Stage Renal Disease ◽

Transient Elastography ◽

Liver Stiffness ◽

Bioelectrical Impedance ◽

Cross Sectional ◽

Before And After ◽

Stage Renal Disease ◽

End Stage ◽

The Impact

Background/Aims: The impact of volume status on liver stiffness measurement (LSM) as measured by transient elastography (TE) as in end-stage renal disease (ESRD) was unclear. We evaluated LSM before and after hemodialysis (HD) and identified the associated factors if the difference of LSM existed. Methods: A cross-sectional study was conducted in ESRD patients on regular HD. Subjects underwent TE and bioelectrical impedance before and after HD. Results: Thirty-six patients were enrolled. Mean (SD) net fluid withdrawal volume (NFWV) per session was 2.55 (0.9) l. Median (range) pre- and post-HD LSMs were 5.38 (2.8-25.7) and 5.4 (2.8-26) kPa, respectively (p = 0.712). Mean differences of pre- and post-HD LSMs correlated with NFWV (r = 0.49, 95% CI 0.19-0.71, p = 0.002). Conclusion: In ESRD on regular HD, LSM is not affected by HD. TE can be done before or after HD with similar results. However, fluid excess at pre-HD can cause inaccurately high LSM.

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Growth restriction in the rat alters expression of metabolic genes during postnatal cardiac development in a sex-specific manner

Physiological Genomics ◽

10.1152/physiolgenomics.00095.2012 ◽

2013 ◽

Vol 45 (3) ◽

pp. 99-105 ◽

Cited By ~ 16

Author(s):

Glenn D. Wadley ◽

Glenn K. McConell ◽

Craig A. Goodman ◽

Andrew L. Siebel ◽

Kerryn T. Westcott ◽

...

Keyword(s):

Gene Expression ◽

Glucose Transport ◽

Mitochondrial Biogenesis ◽

Cardiac Development ◽

Growth Restriction ◽

Antioxidant Defenses ◽

Postnatal Life ◽

Male And Female ◽

Glut 1 ◽

The Impact

This study investigated the impact of uteroplacental insufficiency and growth restriction on the expression of genes related to mitochondrial biogenesis, glucose transport, and antioxidant defenses in cardiac tissue at embryonic day 20 (E20) and postnatal days 1, 7, and 35 in male and female Wistar rats (8–10 per group). Bilateral uterine vessel ligation to induce growth restriction (Restricted) or sham surgery was performed at pregnancy day 18. In male and female Controls, expression of most cardiac genes decreased during postnatal life, including genes involved in mitochondrial biogenesis regulation such as PGC-1α, NRF-2, and mtTFA and the glucose transporter GLUT-1 ( P < 0.05). However, the pattern of gene expression during cardiac development differed in male and female Restricted rats compared with their respective Controls. These effects of restriction were observed at postnatal day 1, with female Restricted rats having delayed reductions in PGC-1α and GLUT-1, whereas males had exacerbated reductions in PGC-1α and mtTFA ( P < 0.05). By day 35, cardiac gene expression in Restricted hearts was similar to Controls, except for expression of the antioxidant enzyme MnSOD, which was significantly lower in both sexes. In summary, during postnatal life male and female Control rats have similar patterns of expression for genes involved in mitochondrial biogenesis and glucose transport. However, following uteroplacental insufficiency these gene expression patterns diverge in males and females during early postnatal life, with MnSOD gene expression reduced in later postnatal life.

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Evolution of gene expression variance during adaptation to high temperature in Drosophila

10.1101/2021.01.19.427270 ◽

2021 ◽

Cited By ~ 1

Author(s):

Wei-Yun Lai ◽

Christian Schlötterer

Keyword(s):

Gene Expression ◽

Natural Populations ◽

Selection Response ◽

Phenotypic Variance ◽

Adaptive Responses ◽

Genetic Redundancy ◽

Before And After ◽

Polygenic Adaptation ◽

The Impact ◽

Expression Variance

AbstractShifts in trait means are widely considered as evidence for adaptive responses, but the impact on phenotypic variance remains largely unexplored. Here, we studied gene expression variance of Drosophila simulans males before and after 100 generations of adaptation to a novel hot laboratory environment. In each of the two independently evolved replicate populations the variance of about 150 genes changed significantly (mostly reduction). Although different genes were affected in both replicates, these genes are related to digestion in the gut. This non-parallel selection response on the gene level in combination with a convergent response at a higher phenotypic level reflects genetic redundancy, a characteristic hallmark of polygenic adaptation. We propose that the constant and simple food source in the laboratory resulted in selection for reduced variance in digestive genes. In natural populations adaptation to diverse types of food may be beneficial, resulting in higher phenotypic variance. This empirical evidence of phenotypic variance being the direct target of selection during adaptation has important implications for strategies to identify selection signatures.

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The impact of rare variation on gene expression across tissues

Nature ◽

10.1038/nature24267 ◽

2017 ◽

Vol 550 (7675) ◽

pp. 239-243 ◽

Cited By ~ 112

Author(s):

Xin Li ◽

◽

Yungil Kim ◽

Emily K. Tsang ◽

Joe R. Davis ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variants ◽

Rare Variants ◽

Disease Risk ◽

Association Studies ◽

Genetic Association Studies ◽

Sequencing Data ◽

Common Genetic Variants ◽

Coding Variants ◽

The Impact

Abstract Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1,2,3,4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8,9,10,11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

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