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BMJ Open Diabetes Research & Care May 2024ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing...
INTRODUCTION
ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not.
RESEARCH DESIGN AND METHODS
Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year.
RESULTS
The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR.
CONCLUSIONS
Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD.
TRIAL REGISTRATION NUMBER
UMIN000011525.
Topics: Humans; Male; Female; Diabetic Nephropathies; Angiotensin-Converting Enzyme 2; Biomarkers; Middle Aged; Glomerular Filtration Rate; Peptidyl-Dipeptidase A; Aged; Prognosis; Disease Progression; Follow-Up Studies
PubMed: 38816205
DOI: 10.1136/bmjdrc-2024-004237 -
Deutsches Arzteblatt International Jul 2024Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most... (Review)
Review
BACKGROUND
Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most serious consequence is generally not the development of end-stage renal failure, but rather the markedly increased cardiovascular risk as kidney function declines.
METHODS
This review is based on the findings of a selective search in PubMed for literature about the treatment options for CRI, and on our overview of the existing guideline recommendations on diagnostic testing.
RESULTS
Patients with diabetes mellitus and arterial hypertension are at especially high risk of developing CRI. For these patients, some of the guidelines recommend regular testing for albuminuria and measurement of the glomerular filtration rate (GFR), though sometimes only when specific risk constellations are present. The treatment of CRI has evolved in recent years. At first, aside from general measures, only RAS inhibitors were available as a specific therapy for CRI. With the extension of the approval of SGLT-2 inhibitors to non-diabetic CRI patients, the options for treatment have become wider. Two randomized controlled trials have revealed the benefit of SGLT-2 inhibitors with respect to their respective primary endpoints: time to a specified eGFR reduction and renal/cardiovascular death (HR 0.61 [0.51; 0.72] and 0.72 [0.64; 0.82]). The potential side effects and contraindications of SGLT-2 inhibitors must be taken into account. A further treatment option for diabetics with CRI has become available with the approval of the non-steroidal mineralocorticoid receptor antagonist finerenone.
CONCLUSION
In patients with risk factors, renal function should be regularly tested.
PubMed: 38814568
DOI: 10.3238/arztebl.m2024.0072 -
Frontiers in Endocrinology 2024Chronic kidney disease (CKD) is a common complication among individuals with hypertension. We aimed to identify the prevalence of CKD and the sex and race disparities...
BACKGROUND
Chronic kidney disease (CKD) is a common complication among individuals with hypertension. We aimed to identify the prevalence of CKD and the sex and race disparities within the hypertensive population in the United States from 2001-2016.
METHODS
A total of 16,148 participants with hypertension were included, representing 561,909,480 individuals from the U.S. population between 2001 and 2016, as documented in the National Health and Nutrition Examination Survey. The prevalence of albuminuria and CKD stage were assessed using survey-weighted general linear regression analysis. Heterogeneity in the CKD stage among the hypertensive population, stratified by sex and race, was identified through survey-weighted logistic regression analysis.
RESULTS
Overall, the prevalence of albuminuria remained stable (p for trend = 0.3196), and changes in the CKD stage were minimal (p for trend > 0.05) from 2001-2016. In the analysis of CKD stage heterogeneity by sex and race, the prevalence of CKD was higher among women than men and higher among individuals of other races combined than non-Hispanic Whites, but the differences were not statistically significant.
CONCLUSION
The overall CKD stage within the hypertensive population plateaued between 2001 and 2016. Our findings highlight the importance of continuous monitoring and potential refinement of renoprotection strategies in individuals with hypertension to mitigate the persistent burden of CKD and address health disparities among different demographic groups.
Topics: Humans; Male; Female; Renal Insufficiency, Chronic; Hypertension; United States; Prevalence; Middle Aged; Adult; Nutrition Surveys; Aged; Sex Factors; Racial Groups; Health Status Disparities
PubMed: 38812816
DOI: 10.3389/fendo.2024.1378631 -
Frontiers in Immunology 2024The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the...
OBJECTIVE
The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression.
METHODS
A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed.
RESULTS
Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened.
CONCLUSION
Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.
Topics: Hepatitis A Virus Cellular Receptor 2; Humans; Diabetic Nephropathies; Female; Middle Aged; Male; Animals; Mice; T-Lymphocytes; Aged; Adult; Inflammation; Kidney; Mice, Inbred C57BL; Disease Progression
PubMed: 38812511
DOI: 10.3389/fimmu.2024.1365226 -
Scientific Reports May 2024This study aims to examine whether hypovitaminosis D was associated with cognitive impairment among chronic kidney patients with different level of albuminuria. This...
This study aims to examine whether hypovitaminosis D was associated with cognitive impairment among chronic kidney patients with different level of albuminuria. This population-based cross-sectional study was conducted on elderly (over 60 years old) with urine albumin to creatinine ratio (UACR) ≥ 30 mg/g from 2011 to 2014 in the US National Health and Nutrition Examination Survey (NHANES). Cognitive function was assessed by the Consortium to Establish a Registry for Alzheimer's Disease Word List Learning (CERAD). Subjects were divided into 2 groups according to the absence or presence of cognitive impairment and a propensity score matching (PSM) was further conducted. The association was assessed with Spearman correlation and logistic regression analysis. The positive association of 25-hydroxyvitamin D3 (25(OH)D3) and cognitive score was presented. PSM analysis revealed that a higher level of 25(OH)D3 correlated to a better cognitive function in CKD patients with albuminuria, especially in patients with 30 mg/g ≤ UACR < 300 mg/g. This study indicated that a low 25(OH)D3 level was associated with poor cognitive performance, especially in patients with microalbuminuria. Thus, early diagnosis of vitamin D insufficiency and an effective intervention might be a useful therapeutic strategy to prevent cognitive decline in patients with the progression of renal dysfunction.
Topics: Humans; Female; Male; Renal Insufficiency, Chronic; Cognitive Dysfunction; Aged; Cross-Sectional Studies; Calcifediol; Middle Aged; Albuminuria; Vitamin D Deficiency; Aged, 80 and over; Nutrition Surveys
PubMed: 38811765
DOI: 10.1038/s41598-024-63350-y -
PloS One 2024Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we...
Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we analyzed global, podocyte-specific, and inducible Dach1 knockout mice. Global Dach1 knockout (Dach1-/-) mice were assessed immediately after birth because they die within a day. The kidneys of Dach1-/- mice were slightly smaller than those of control mice but maintained a normal structure and normal podocyte phenotypes, including ultrastructure. To study the role of Dach1 in mature podocytes, we generated Dach1 knockout mice by mating Dach1fl/fl mice with Nphs1-Cre or ROSA-CreERT2 mice. Due to inefficient Cre recombination, only a small number of podocytes lacked Dach1 staining in these mice. However, all eleven Nphs1-Cre/Dach1fl/fl mice displayed abnormal albuminuria, and seven (63%) of them developed focal segmental glomerulosclerosis. Among 13 ROSA-CreERT2/Dach1fl/fl mice, eight (61%) exhibited abnormal albuminuria after treatment with tamoxifen, and five (38%) developed early sclerotic lesions. These results indicate that while Dach1 does not determine the fate of differentiation into podocytes, it is indispensable for maintaining the normal integrity of mature podocytes.
Topics: Animals; Podocytes; Mice; Mice, Knockout; Albuminuria; Cell Differentiation; Glomerulosclerosis, Focal Segmental; Eye Proteins
PubMed: 38805434
DOI: 10.1371/journal.pone.0303910 -
Diabetes, Metabolic Syndrome and... 2024Elevated urine albumin-to-creatinine ratio (UACR) is an established risk factor for microvascular disease in the general population. However, it is unclear whether UACR...
PURPOSE
Elevated urine albumin-to-creatinine ratio (UACR) is an established risk factor for microvascular disease in the general population. However, it is unclear whether UACR is associated with arterial stiffness in diabetes. We aimed to assess the relationship between UACR levels and the risk of arterial stiffness in patients with diabetes.
METHODS
From July 2021 to February 2023, a total of 1039 participants were assessed for the risk of arterial stiffness, which was evaluated by brachial-ankle pulse wave velocity (baPWV). The value of UACR≥30 mg/g was defined as high UACR. The UACR level had an abnormal distribution and was log2-transformed for analyses to reduce skewness and volatility. High baPWV was evaluated as categorical variables divided by the highest quartile of the values by sex. The relationship between UACR and arterial stiffness was analyzed by linear curve fitting analyses. Multiple logistic regression models were used to analyze the crude and adjusted odds ratio (OR) of UACR for high baPWV with 95% confidence interval (CI). In addition to applying non-adjusted and multivariate-adjusted models, interaction and stratified analyses were also carried out.
RESULTS
The baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group (1861.84 ± 439.12 cm/s vs 1723.13 ± 399.63 cm/s, <0.001). Adjusted smoothed plots suggested that there are linear relationships between log2-transformed UACR and high baPWV, and Spearman correlation coefficient was 0.226 (0.176-0.276, <0.001). The OR (95% CI) between log2-transformed UACR and high baPWV were 1.26 (1.19-1.33, <0.001), and 1.16 (1.08-1.25, <0.001) respectively in diabetic patients before and after adjusting for potential confounders.
CONCLUSION
The elevated UACR was associated with arterial stiffness in Chinese patients with diabetes.
PubMed: 38803641
DOI: 10.2147/DMSO.S457883 -
Frontiers in Pharmacology 2024Diabetic kidney disease (DKD) is one of the chronic microvascular complications caused by diabetes, which is characterized by persistent albuminuria and/or progressive... (Review)
Review
Diabetic kidney disease (DKD) is one of the chronic microvascular complications caused by diabetes, which is characterized by persistent albuminuria and/or progressive decline of estimated glomerular filtration rate (eGFR), and has been the major cause of dialysis around the world. At present, although the treatments for DKD including lifestyle modification, glycemic control and even using of Sodium-glucose cotransporter 2 (SGLT2) inhibitors can relieve kidney damage caused to a certain extent, there is still a lack of effective treatment schemes that can prevent DKD progressing to ESRD. It is urgent to find new complementary and effective therapeutic agents. Growing animal researches have shown that mitophagy makes a great difference to the pathogenesis of DKD, therefore, exploration of new drugs that target the restoration of mitophagy maybe a potential perspective treatment for DKD. The use of Chinese botanical drugs (CBD) has been identified to be an effective treatment option for DKD. There is growing concern on the molecular mechanism of CBD for treatment of DKD by regulating mitophagy. In this review, we highlight the current findings regarding the function of mitophagy in the pathological damages and progression of DKD and summarize the contributions of CBD that ameliorate renal injuries in DKD by interfering with mitophagy, which will help us further explain the mechanism of CBD in treatment for DKD and explore potential therapeutic strategies for DKD.
PubMed: 38803440
DOI: 10.3389/fphar.2024.1360179 -
Frontiers in Medicine 2024Preeclampsia (PE), a pregnancy specific syndrome, is defined as new-onset hypertension (≥140/90 mmHg) and proteinuria diagnosed after gestational week 20 or...
BACKGROUND
Preeclampsia (PE), a pregnancy specific syndrome, is defined as new-onset hypertension (≥140/90 mmHg) and proteinuria diagnosed after gestational week 20 or new-onset pre-eclampsia associated signs in the absence of proteinuria, and it may tend to present as late as 4-6 weeks' postpartum period. It is a leading cause of maternal mortality in both developed and developing countries. In order to prevent PE, the disease must be diagnosed at its earliest stage, however, the triads of high blood pressure, edema and albuminuria is neither specific nor sensitive enough for diagnosing the disease. Lactate dehydrogenase (LDH) is useful biochemical marker reflecting the occurrence of complications associated with preeclampsia. Besides, it has been suggested as potential biomarker to predict the severity of preeclampsia and as indicator of multi-organ involvement. The aim of this study was to investigate the diagnostic accuracy of LDH, which is affordable and easy to test, as a potential clinical biomarker to predict onset of preeclampsia.
METHODS
A hospital based cross-sectional study was conducted as of September 9 to December 24, 2022 at Debre Birhan Comprehensive Specialized Hospital (DBCSH). A total of 132 study subjects (66 preeclamptic and 66 normotensive controls) were enrolled in the study. A receiver operating characteristics (ROC) curve was used to calculate the area under the curve (AUC) and determine diagnostic accuracy of LDH. Youden's index was used to identify an optimal cut-off point for LDH in detecting preeclampsia associated complications.
RESULT
AUC for LDH was found to be 0.963 (95% CI, 0.91, 1.0; = 0.000) from ROC curve analysis. An optimal cut-off point for LDH was 376.5 U/L having a sensitivity and specificity of 87.5 and 90.8%, respectively.
CONCLUSION
Serum LDH had an AUC of greater than 0.8 and showed good diagnostic accuracy in predicting development of preeclampsia. Disease duration, gestational age, systolic and diastolic blood pressure among enormous number of predictor variables had association with serum level of LDH.
PubMed: 38799154
DOI: 10.3389/fmed.2024.1240848 -
Human In Vitro Oxidized Low-Density Lipoprotein (oxLDL) Increases Urinary Albumin Excretion in Rats.International Journal of Molecular... May 2024Hypercholesterolemia-associated oxidative stress increases the formation of oxidized low-density lipoprotein (oxLDL), which can affect endothelial cell function and...
Hypercholesterolemia-associated oxidative stress increases the formation of oxidized low-density lipoprotein (oxLDL), which can affect endothelial cell function and potentially contribute to renal dysfunction, as reflected by changes in urinary protein excretion. This study aimed to investigate the impact of exogenous oxLDL on urinary excretion of albumin and nephrin. LDL was isolated from a patient with familial hypercholesterolemia (FH) undergoing lipoprotein apheresis (LA) and was oxidized in vitro with Cu (II) ions. Biochemical markers of LDL oxidation, such as TBARS, conjugated dienes, and free ε-amino groups, were measured. Wistar rats were treated with a single intraperitoneal injection of PBS, LDL, or oxLDL (4 mg of protein/kg b.w.). Urine was collected one day before and two days after the injection. We measured blood lipid profiles, urinary protein excretion (specifically albumin and nephrin), and markers of systemic oxidative stress (8-OHdG and 8-iso-PGF2α). The results showed that injection of oxLDL increased urinary albumin excretion by approximately 28% (310 ± 27 μg/24 h vs. 396 ± 26 μg/24 h, = 0.0003) but had no effect on nephrin excretion. Neither PBS nor LDL had any effect on urinary albumin or nephrin excretion. Additionally, oxLDL did not affect systemic oxidative stress. In conclusion, hypercholesterolemia may adversely affect renal function through oxidatively modified LDL, which interferes with the renal handling of albumin and leads to the development of albuminuria.
Topics: Lipoproteins, LDL; Animals; Humans; Rats; Rats, Wistar; Albuminuria; Oxidative Stress; Male; Oxidation-Reduction; Membrane Proteins; Hyperlipoproteinemia Type II
PubMed: 38791535
DOI: 10.3390/ijms25105498