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BMC Medicine Dec 2023Solute carrier family 13 member 5 (SLC13A5) is a Na-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has...
BACKGROUND
Solute carrier family 13 member 5 (SLC13A5) is a Na-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts.
METHODS
The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals.
RESULTS
We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns.
CONCLUSIONS
This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.
Topics: Humans; Biomarkers; Calcium; Citrates; Creatinine; Cystatin C; Drug Development; Genome-Wide Association Study; Kidney; Mendelian Randomization Analysis; Renal Insufficiency, Chronic; Symporters
PubMed: 38110950
DOI: 10.1186/s12916-023-03227-5 -
International Journal of Cardiology Aug 2023Cardiometabolic index (CMI) is recently considered to have certain significance in the screening of diabetes, atherosclerosis, and renal dysfunction. Therefore, this...
PURPOSE
Cardiometabolic index (CMI) is recently considered to have certain significance in the screening of diabetes, atherosclerosis, and renal dysfunction. Therefore, this study intends to explore the relationship between CMI and the risk of albuminuria.
METHODS
This is a cross-sectional study involving 2732 elderly people (age ≥ 60). The research data are from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Calculate CMI index: Triglyceride (TG) (mmol/L)/ High density lipid-cholesterol (HDLC) (mmol/L) × WHtR.
RESULTS
The CMI level in microalbuminuria group was significantly higher than that in normal albuminuria group (P < 0.05 or P < 0.01), whether in the general population or in diabetes and hypertensive population respectively. The proportion of abnormal microalbuminuria increased gradually with the increase of CMI tertile interval (P < 0.01). Correlation analysis showed that CMI was positively correlated with urinary albumin-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine (Scr), and negatively correlated with estimated glomerular filtration rate (eGFR). With the occurrence of albuminuria as the dependent variable, weighted logistic regression analysis showed that CMI was an independent risk factor for microalbuminuria. Weighted smooth curve fitting showed that CMI index was linearly related to the risk of microalbuminuria. Subgroup analysis and interaction test showed that they participated in this positive correlation.
CONCLUSIONS
Obviously, CMI is independently associated with microalbuminuria, suggesting that CMI, a simple indicator, can be used for risk assessment of microalbuminuria, especially in diabetes patients.
Topics: Aged; Humans; Nutrition Surveys; Albuminuria; Cross-Sectional Studies; Hypertension; Diabetes Mellitus; Albumins; Kidney
PubMed: 37059309
DOI: 10.1016/j.ijcard.2023.04.017 -
Clinica Chimica Acta; International... Jun 2024Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although... (Review)
Review
Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although microalbuminuria is considered the best non-invasive marker for DN, better predictive markers are needed of sufficient sensitivity and specificity to detect disease in general and in early disease specifically. Even prior to appearance of microalbuminuria, urinary biomarkers increase in diabetics and can serve as accurate nephropathy biomarkers even in normoalbuminuria. In this review, a number of novel urine biomarkers including those reflecting kidney damage caused by glomerular/podocyte damage, tubular damage, oxidative stress, inflammation, and intrarenal renin-angiotensin system activation are discussed. Our review also includes emerging biomarkers such as urinary microRNAs. These short noncoding miRNAs regulate gene expression and could be utilized to identify potential novel biomarkers in DN development and progression. .
PubMed: 38844018
DOI: 10.1016/j.cca.2024.119762 -
MedRxiv : the Preprint Server For... Nov 2023The aim was to compare cardiometabolic health between Asian American children and Non-Hispanic White (NHW) children as well as to compare cardiometabolic health among...
BACKGROUND
The aim was to compare cardiometabolic health between Asian American children and Non-Hispanic White (NHW) children as well as to compare cardiometabolic health among Asian American children by birthplace.
METHODS
Children aged 6-17 years enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2011-2018 who self-identified as non-Hispanic Asian and NHW were included. Among Asian Americans, place of birth was defined as foreign-born vs United States (US)-born. Regression models were adjusted for age, sex, household income, food insecurity, passive smoke exposure, and body mass index (BMI) z-score.
RESULTS
Among 3369 children, 8.4% identified as Asian American (age 11.7 years) and 91.6% identified as NHW (age 11.7 years). Compared to NHW children, Asian American children had significantly lower BMI z-scores and odds of obesity. Asian American children had higher HOMA-IR and uric acid, and greater odds of dyslipidemia, microalbuminuria and glomerular hyperfiltration compared to NHW children. Among Asian Americans, 30.5% were foreign-born. Compared to foreign-born Asian American children, US-born Asian American children had significantly higher non-HDL, triglycerides, HOMA-IR and uric acid, lower HDL, and lower odds of hyperfiltration. There were no differences in blood pressure by racial group or place of birth.
CONCLUSIONS
Although Asian American children have lower odds of obesity, they have significantly worse glucose intolerance, higher serum uric acid levels, more dyslipidemia and more microalbuminuria compared to NHW children. US-born Asian American children have worse cardiometabolic health profiles compared to foreign-born Asian Americans.
PubMed: 37986922
DOI: 10.1101/2023.11.11.23298417 -
International Urology and Nephrology Oct 2023To investigate the prevalence of microalbuminuria and factors associated with microalbuminuria in Graves' Disease (GD).
PURPOSE
To investigate the prevalence of microalbuminuria and factors associated with microalbuminuria in Graves' Disease (GD).
METHODS
This cross-sectional and single-center study included 99 patients with GD and 47 healthy controls (HC). Exclusion criteria such as active infection, uncontrolled diabetes, and chronic kidney disease were applied to the participants. The participants' clinical findings, comorbidities, drug use, laboratory tests, and thyroid antibody levels were recorded. Spot urine samples were collected and stored at - 80 ℃ to analyze the presence of microalbuminuria.
RESULTS
The prevalence of microalbuminuria in patients with GD was 12.1%. The median microalbumin/creatinine ratio in spot urine (UACR) in patients with GD (9.49 mg/g [5.09-18.10]) was higher than in the HC group (7.99 mg/g [3.48-12.88], p = 0.033). UACR was correlated with thyroid-stimulating hormone receptor antibody (TRAb), thyroid-stimulating hormone (TSH), and free triiodothyronine (FT3) levels (p = 0.020, p = 0.006, p = 0.009 respectively). In the regression analysis, only the relationship between TRAb level and UACR remained (p = 0.040).
CONCLUSION
This study demonstrates an increased prevalence of microalbuminuria in patients with GD. There was a significant correlation between microalbuminuria and TRAb level in patients with GD. This relationship suggests that one of the underlying mechanisms of microalbuminuria seen in patients with GD may be autoimmunity.
Topics: Humans; Autoantibodies; Cross-Sectional Studies; Graves Disease; Thyrotropin; Kidney
PubMed: 37093438
DOI: 10.1007/s11255-023-03600-6 -
Current Opinion in Nephrology and... Sep 2023Approximately 1.28 billion people are affected by hypertension globally and the incidence of hypertension is on an upward trajectory with an aging population and... (Review)
Review
PURPOSE OF REVIEW
Approximately 1.28 billion people are affected by hypertension globally and the incidence of hypertension is on an upward trajectory with an aging population and increasing burden of risk factors including obesity. Despite low-cost, highly-effectively, easy-to-treat strategies, it is estimated that ∼720 million people are not receiving the treatment they need for optimal hypertension management. Several factors contribute to this including an unwillingness to be treated for an asymptomatic condition.
RECENT FINDINGS
Biomarkers such as troponin, B-type Natriuretic Peptide (BNP), N-terminal-pro hormone BNP (NT-proBNP), uric acid, microalbuminuria have been found to be associated with adverse clinical outcomes among individuals with hypertension. Biomarkers also allow for identification of asymptomatic organ damage.
SUMMARY
Biomarkers have the ability to identify higher risk individuals in whom risk-benefit for therapies may be most favorable, helping optimize the net benefit of therapy. Whether biomarkers can help guide therapy intensity and choice remains to be tested.
Topics: Humans; Aged; Hypertension; Biomarkers; Risk Factors; Risk Assessment; Obesity; Peptide Fragments
PubMed: 37382193
DOI: 10.1097/MNH.0000000000000905 -
Journal of Racial and Ethnic Health... Dec 2023The aim was to compare cardiometabolic health between Asian American children and Non-Hispanic White (NHW) children as well as to compare cardiometabolic health among...
BACKGROUND
The aim was to compare cardiometabolic health between Asian American children and Non-Hispanic White (NHW) children as well as to compare cardiometabolic health among Asian American children by birthplace.
METHODS
Children aged 6-17 years enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 who self-identified as non-Hispanic Asian and NHW were included. Among Asian Americans, place of birth was defined as foreign born vs United States (US) born. Regression models were adjusted for age, sex, household income, food insecurity, passive smoke exposure, and body mass index (BMI) z-score.
RESULTS
Among 3369 children, 8.4% identified as Asian American (age 11.7 years) and 91.6% identified as NHW (age 11.7 years). Compared to NHW children, Asian American children had significantly lower BMI z-scores and odds of obesity. Asian American children had higher HOMA-IR, and greater odds of dyslipidemia and microalbuminuria compared to NHW children. Among Asian Americans, 30.5% were foreign born. Compared to foreign-born Asian American children, US-born Asian American children had significantly higher non-HDL, triglycerides, and uric acid, lower HDL, and lower odds of hyperfiltration. There were no differences in blood pressure by racial group or place of birth.
CONCLUSIONS
Although Asian American children have lower odds of obesity, they have significantly worse glucose intolerance, more dyslipidemia, and more microalbuminuria compared to NHW children. US-born Asian American children have worse cardiometabolic health profiles compared to foreign-born Asian Americans.
PubMed: 38147200
DOI: 10.1007/s40615-023-01896-9 -
Frontiers in Endocrinology 2023The potential relationship between Klotho and cognitive function is limited and controversial. This study aimed to quantify the association of Klotho and cognitive...
BACKGROUND
The potential relationship between Klotho and cognitive function is limited and controversial. This study aimed to quantify the association of Klotho and cognitive impairment in chronic kidney disease (CKD) patients with albuminuria.
METHODS
Serum Klotho was measured by enzyme-linked immunosorbent assay. Patients with urine albumin to creatinine ratio (UACR) > 30mg/g from the National Health and Nutrition Survey (NHANES) 2011-2014 were divided into 4 groups according to the quartile of Klotho. Cognitive function was examined using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Digit Symbol Substitution Test (DSST), and Animal Fluency Test. The relationship between Klotho and cognitive function was analyzed by multivariable regression and subgroup analysis.
RESULTS
Among 368 CKD patients with albuminuria, we found that Klotho was negatively associated with creatinine, and positively associated with hemoglobin, and estimated glomerular filtration rate. No significant linear relationship was showed between Klotho (as a continuous variable) and cognitive function. When regarded Klotho as a category variable, patients in the quartile 3 group were at a better cognitive performance for CEARD-word learning subset and DSST, especially in the CKD patients with 30 mg/g < UACR <300 mg/g, but not in participants with UACR > 300 mg/g.
CONCLUSIONS
The increased Klotho was associated with an increased cognitive function in CKD patients with microalbuminuria. Further studies are needed to demonstrate whether Klotho may be a beneficial biomarker of cognitive health and neurodegeneration.
Topics: Humans; Albuminuria; Cognition; Creatinine; Nutrition Surveys; Renal Insufficiency, Chronic; Klotho Proteins
PubMed: 37560310
DOI: 10.3389/fendo.2023.1215977