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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 -
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 -
Clinical Kidney Journal Nov 2023The 'legacy effect' refers to the long-term benefits of intensive therapy that are observed long after the end of clinical trials and trial interventions in chronic... (Review)
Review
The 'legacy effect' refers to the long-term benefits of intensive therapy that are observed long after the end of clinical trials and trial interventions in chronic diseases such as diabetes, hyperlipidaemia and hypertension. It emphasizes the importance of intensive treatment to prevent long-term complications and mortality. In chronic kidney disease (CKD), the legacy effect is evident in various studies. Long-term nephroprotection in diabetes is well documented in major studies in the early stages of diabetes, such as Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC), UK Prospective Diabetes Study (UKPDS) and Intensified Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria (STENO-2). These studies highlight the importance of intensive glycaemic control in reducing microvascular complications, including nephropathy, in patients with recently diagnosed type 1 and type 2 diabetes. However, the legacy effect is less evident in patients with long-term, established diabetes. In chronic glomerulonephritis, studies on immunoglobulin A nephropathy showed that early immunosuppressive treatment could have long-term beneficial effects on kidney function in children and adults with CKD. The Frequent Hemodialysis (FH) and the EXerCise Introduction To Enhance Performance in Dialysis (EXCITE) trials indicated that frequent haemodialysis and a personalized walking exercise program could improve clinical outcomes and reduce the long-term risk of death and hospitalization. The legacy effect concept underscores the importance of intensive intervention in chronic diseases, including CKD. This concept has significant implications for public health and warrants in-depth basic and clinical research to be better understood and exploited in clinical practice. However, its limitations should be considered when interpreting long-term observational data collected after a clinical trial. Appropriate study designs are necessary to investigate an unbiased legacy effect.
PubMed: 37915902
DOI: 10.1093/ckj/sfad186 -
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 -
Indian Heart Journal 2023Microalbuminuria has been elevated as an outcome predictor in cardiovascular medicine. However, due to the small number of studies investigating the association of... (Meta-Analysis)
Meta-Analysis Review
AIM
Microalbuminuria has been elevated as an outcome predictor in cardiovascular medicine. However, due to the small number of studies investigating the association of microalbuminuria and mortality in the coronary heart disease (CHD) population, the prognosis value of microalbuminuria in CHD remains under debate. The objective of this meta-analysis was to investigate the relationship between microalbuminuria and mortality in individuals with CHD.
METHOD
A comprehensive literature search was performed using Pubmed, EuroPMC, Science Direct, and Google Scholar from 2000 to September 2022. Only prospective studies investigating microalbuminuria and mortality in CHD patients were selected. The pooled effect estimate was reported as risk ratio (RR).
RESULTS
5176 patients from eight prospective observational studies were included in this meta-analysis. Individuals with CHD have a greater overall risk of all-cause mortality (ACM) [rR = 2.07 (95% CI = 1.70-2.44); p = 0.0003; I = 0.0%] as well as cardiovascular mortality (CVM) [rR = 3.23 (95% CI = 2.06-4.39), p < 0.0001; I = 0.0%]. Subgroup analysis based on follow-up duration and a subset of CHD patients were similarly associated with an increased risk of ACM.
CONCLUSION
This meta-analysis indicates that microalbuminuria is associated with a higher risk of mortality in individuals with CHD. Microalbuminuria can serve as a predictor of poor outcomes in CHD patients.
Topics: Humans; Prospective Studies; Coronary Disease; Prognosis; Heart; Risk Factors; Observational Studies as Topic
PubMed: 37207828
DOI: 10.1016/j.ihj.2023.05.006 -
International Journal of Biological... 2024TGF-β/Smad3 signaling plays a critical role in type 2 diabetes (T2D) and type 2 diabetic nephropathy (T2DN), but treatment by specifically targeting Smad3 remains...
TGF-β/Smad3 signaling plays a critical role in type 2 diabetes (T2D) and type 2 diabetic nephropathy (T2DN), but treatment by specifically targeting Smad3 remains unexplored. To develop a new Smad3-targeted therapy for T2D and T2DN, we treated db/db mice at the pre-diabetic or established diabetic stage with a pharmacological Smad3 inhibitor SIS3. The therapeutic effect and mechanisms of anti-Smad3 treatment on T2D and T2DN were investigated. We found that anti-Smad3 treatment on pre-diabetic db/db mice largely attenuated both T2D and T2DN by markedly reducing blood glucose levels, and inhibiting the elevated serum creatinine, microalbuminuria, and renal fibrosis and inflammation. Unexpectedly, although SIS3 treatment on the established diabetic db/db mice inhibited T2DN but did not significantly improve T2D. Mechanistically, we uncovered that inhibition of T2DN in SIS3-treated db/db mice was associated with effectively restoring the balance of TGF-β/Smad signaling by inhibiting Smad3 while increasing Smad7, thereby suppressing Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation via lncRNA Erbb4-IR and LRN9884-dependent mechanisms. We also revealed that inhibition of islet β cell injury by preventing the loss of islet Pax 6 could be the mechanism through which the pre-diabetic treatment, rather than the late SIS3 treatment on db/db mice significantly improved the T2D phenotype.
Topics: Mice; Animals; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Prediabetic State; Inflammation; Transforming Growth Factor beta; Fibrosis; Smad3 Protein; Kidney
PubMed: 38164169
DOI: 10.7150/ijbs.87820 -
Open Forum Infectious Diseases Jul 2023The kidney is a common target for human immunodeficiency virus (HIV), making renal disease a common noninfectious complication of HIV. Microalbuminuria is an important...
BACKGROUND
The kidney is a common target for human immunodeficiency virus (HIV), making renal disease a common noninfectious complication of HIV. Microalbuminuria is an important marker that can detect early renal damage. Timely detection of microalbuminuria is important to initiate renal management and stop the progression of renal dysfunction in people with HIV. Limited data are available about renal abnormalities in people with perinatal HIV infection. The objective of this study was to determine the prevalence of microalbuminuria in a cohort of perinatally HIV-infected children and young adults receiving combination antiretroviral therapy and investigate correlations between microalbuminuria and clinical and laboratory findings.
METHODS
This was a retrospective study of 71 patients with HIV followed in an urban pediatric HIV clinic in Houston, Texas, between October 2007 and August 2016. Demographic, clinical, and laboratory data were compared between subjects with persistent microalbuminuria (PM) and those without. PM is defined as a microalbumin-to-creatinine ratio ≥30 mg/g on at least 2 occasions separated by at least 1 month.
RESULTS
Sixteen of 71 patients (23%) met the definition of PM. In univariate analysis, patients with PM had significantly higher CD8 T-cell activation and lower CD4 T-cell nadir. Multivariate analysis demonstrated increased microalbuminuria to be independently associated with older age and CD8 T-cell activation measured as CD8HLA-DR T-cell percentage.
CONCLUSIONS
Older age and increased activation of CD8HLA-DR on T cells correlate with presence of microalbuminuria in this cohort of HIV-infected patients.
PubMed: 37426950
DOI: 10.1093/ofid/ofad333 -
Microbiology Spectrum Aug 2023Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved...
Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved in the development of diabetic kidney diseases (DKD). The objective of this study was to determine bacterial taxa biomarkers during the progression of DKD by investigating bacterial compositional changes in early and late DKD. 16S rRNA gene sequencing was performed on fecal samples, including the diabetes mellitus (DM), DNa (early DKD), and DNb (late DKD) groups. Taxonomic annotation of microbial composition was performed. Samples were sequenced on the Illumina NovaSeq platform. At the genus level, we found counts of , , and were significantly elevated both in the DNa group (0.0001, 0.0007, and 0.0174, respectively) and the DNb group (0.0001, 0.0012, and 0.0003, respectively) compared with those in the DM group. Only the level of was significantly decreased in the DNa group than the DM group and in the DNb group than the DNa group. Counts of , were significantly decreased in the DNa group compared with those in the DM group (0.001 and 0.006, respectively) and in the DNb group compared with those in the DM group (0.0001 and 0.003, respectively). Levels of , and were positively correlated with an estimated glomerular filtration rate (eGFR), but negatively correlated with microalbuminuria (MAU), 24 h urinary protein quantity (24hUP), and serum creatinine (Scr). Moreover, the areas under the curve (AUCs) of and were 83.33% and 80.77%, respectively, for the DM and DNa cohorts, respectively. Notably, the largest AUC for DNa and DNb cohorts was also that of at 83.60%. Gut microbiota dysbiosis was found in the early and late stages of DKD, especially in the early stage. may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD. It is not clear as to whether gut microbiota dysbiosis is involved in the progression of DKD. This study may be the first to explore gut microbiota compositional changes in diabetes, early-DKD, and late DKD. We identify different gut microbial characteristics during different stages of DKD. Gut microbiota dysbiosis is found in the early and late stages of DKD. may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD, although further studies are warranted to illustrate these mechanisms.
Topics: Diabetic Nephropathies; Humans; Male; Female; Middle Aged; Gastrointestinal Microbiome; Clostridiales; Biomarkers; Diabetes Mellitus; Bacteria; Feces; Kidney Failure, Chronic
PubMed: 37341590
DOI: 10.1128/spectrum.00382-23