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Diabetes & Vascular Disease Research 2021Type 2 diabetes mellitus is a pathology of heterogeneous etiology characterized by hyperglycemia resulting from lack of insulin action, insulin secretion, or both, and... (Review)
Review
Type 2 diabetes mellitus is a pathology of heterogeneous etiology characterized by hyperglycemia resulting from lack of insulin action, insulin secretion, or both, and the population with diabetes mellitus is predicted to be about 439 million worldwide by 2030. Prolong diabetes has been related with microvascular complications especially diabetic nephropathy. DN is the most common complication of type 2 diabetes mellitus, and it is the leading cause of end-stage renal disease worldwide. It is crucial to diagnose patients who are more sensible to develop DN for better control of the process of disease. Several factors and mechanisms contribute to the development and outcome of diabetic nephropathy. Microalbuminuria is an early marker of DN and use it as a routine for screening, but the renal damages may be happening even without microalbuminuria. There are several significant kidney damage and disease biomarkers which helps in early detection of DN. An early biomarker may allow earlier diagnosis, treatment reduces DN prevalence and slows DN progression. Therefore, this review focuses on laboratory biomarkers that are earlier, more validation of an early and specific biomarker could potentially make it possible for early diagnosis, treatment, and retardation of progression of diabetic nephropathy.
Topics: Albuminuria; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Early Diagnosis; Humans
PubMed: 34791910
DOI: 10.1177/14791641211058856 -
Frontiers in Immunology 2022Systemic immune-inflammation index (SII) is a novel inflammatory marker, and inflammation has been reported to be related with renal damage. We aimed to investigate the...
BACKGROUND
Systemic immune-inflammation index (SII) is a novel inflammatory marker, and inflammation has been reported to be related with renal damage. We aimed to investigate the possible relationship between SII and albuminuria.
METHODS
The present cross-sectional study was conducted among adults with complete data about SII and urinary albumin-to-creatinine ratio (ACR) in 2005-2018 National Health and Nutrition Examination Survey (NHANES). SII was calculated as the platelet count × neutrophil count/lymphocyte count. Albuminuria was defined as ACR >30mg/g. Weighted multivariable regression analysis and subgroup analysis were conducted to explore the independent relationship between SII and albuminuria.
RESULTS
A total of 36,463 individuals were included in our analysis; 9.56% participants were categorized as having albuminuria overall and increased with the higher SII tertiles (tertile 1, 7.83%; tertile 2, 8.49%; tertile 3, 12.13%; p for trend <0.0001). Multivariable logistic regression showed that a higher SII level was associated with increased likelihood of albuminuria independently (OR = 1.31; 95% CI, 1.17-1.48, p<0.0001) after full adjustment. Subgroup analysis and interaction test showed that there was no significant dependence of gender, age, body mass index, hypertension, diabetes, non-alcoholic fatty liver disease, and estimated glomerular filtration rate (eGFR) on this positive association (all p for interaction >0.05).
CONCLUSIONS
SII was positively associated with increased urinary albumin excretion in US adults. Further large-scale prospective studies are still needed to analyze the role of SII in albuminuria.
Topics: Adult; Albumins; Albuminuria; Cross-Sectional Studies; Humans; Inflammation; Nutrition Surveys; Serum Albumin, Human
PubMed: 35386695
DOI: 10.3389/fimmu.2022.863640 -
European Heart Journal Feb 2023Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is...
AIMS
Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated.
METHODS AND RESULTS
Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumincreatinine ratio (UACR) 30 mg/gCr and 300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4 and 10.0, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95 confidence interval 0.350.53, P 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings.
CONCLUSION
In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.
Topics: Humans; Prognosis; Albuminuria; Heart Failure; Biomarkers; Natriuretic Peptide, Brain; Hospitalization; Peptide Fragments; Stroke Volume
PubMed: 36148485
DOI: 10.1093/eurheartj/ehac528 -
The Lancet. Diabetes & Endocrinology Feb 2019Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.
METHODS
In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.
FINDINGS
Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (p<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.
INTERPRETATION
Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.
FUNDING
US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.
Topics: Albuminuria; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Kidney Function Tests; Observational Studies as Topic; Prognosis; Risk Factors
PubMed: 30635225
DOI: 10.1016/S2213-8587(18)30313-9 -
JAMA Cardiology Nov 2022Albuminuria, routinely assessed as spot urine albumin-to-creatinine ratio (UACR), indicates structural damage of the glomerular filtration barrier and is associated with... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Albuminuria, routinely assessed as spot urine albumin-to-creatinine ratio (UACR), indicates structural damage of the glomerular filtration barrier and is associated with poor kidney and cardiovascular outcomes. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to reduce UACR in patients with type 2 diabetes, but its use in patients with heart failure (HF) is less well studied.
OBJECTIVE
To analyze the association of empagliflozin with study outcomes across baseline levels of albuminuria and change in albuminuria in patients with HF across a wide range of ejection fraction levels.
DESIGN, SETTING, AND PARTICIPANTS
This post hoc analysis included all patients with HF from the EMPEROR-Pooled analysis using combined individual patient data from the international multicenter randomized double-blind parallel-group, placebo-controlled EMPEROR-Reduced and EMPEROR-Preserved trials. Participants in the original trials were excluded from this analysis if they were missing baseline UACR data. EMPEROR-Preserved was conducted from March 27, 2017, to April 26, 2021, and EMPEROR-Reduced was conducted from April 6, 2017, to May 28, 2020. Data were analyzed from January to June 2022.
INTERVENTIONS
Randomization to empagliflozin or placebo.
MAIN OUTCOMES AND MEASURES
New-onset macroalbuminuria and regression to normoalbuminuria and microalbuminuria.
RESULTS
A total of 9673 patients were included (mean [SD] age, 69.9 [10.4] years; 3551 [36.7%] female and 6122 [63.3%] male). Of these, 5552 patients had normoalbuminuria (UACR <30 mg/g) and 1025 had macroalbuminuria (UACR >300 mg/g). Compared with normoalbuminuria, macroalbuminuria was associated with younger age, races other than White, obesity, male sex, site region other than Europe, higher levels of N-terminal pro-hormone brain natriuretic peptide and high-sensitivity troponin T, higher blood pressure, higher New York Heart Association class, greater HF duration, more frequent previous HF hospitalizations, diabetes, hypertension, lower eGFR, and less frequent use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and mineralocorticoid receptor antagonists. An increase in events was observed in individuals with higher UACR levels. The association of empagliflozin with cardiovascular mortality or HF hospitalization was consistent across UACR categories (hazard ratio [HR], 0.80; 95% CI, 0.69-0.92 for normoalbuminuria; HR, 0.74; 95% CI, 0.63-0.86 for microalbuminuria; HR, 0.78; 95% CI, 0.63-0.98 for macroalbuminuria; interaction P trend = .71). Treatment with empagliflozin was associated with lower incidence of new macroalbuminuria (HR, 0.81; 95% CI, 0.70-0.94; P = .005) and an increase in rate of remission to sustained normoalbuminuria or microalbuminuria (HR, 1.31; 95% CI, 1.07-1.59; P = .009) but not with a reduction in UACR in the overall population; however, UACR was reduced in patients with diabetes, who had higher UACR levels than patients without diabetes (geometric mean for diabetes at baseline, 0.91; 95% CI, 0.85-0.98 and for no diabetes at baseline, 1.08; 95% CI, 1.01-1.16; interaction P = .008).
CONCLUSIONS AND RELEVANCE
In this post hoc analysis of a randomized clinical trial, compared with placebo, empagliflozin was associated with reduced HF hospitalizations or cardiovascular death irrespective of albuminuria levels at baseline, reduced progression to macroalbuminuria, and reversion of macroalbuminuria.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT03057977 and NCT03057951.
Topics: Humans; Male; Female; Aged; Albuminuria; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Heart Failure
PubMed: 36129693
DOI: 10.1001/jamacardio.2022.2924 -
Molecular Therapy : the Journal of the... Aug 2019Albumin absorbed by renal tubular epithelial cells induces inflammation and plays a key role in promoting diabetic kidney disease (DKD) progression. Macrophages are...
Albumin absorbed by renal tubular epithelial cells induces inflammation and plays a key role in promoting diabetic kidney disease (DKD) progression. Macrophages are prominent inflammatory cells in the kidney, and their role there is dependent on their phenotypes. However, whether albuminuria influences macrophage phenotypes and underlying mechanisms during the development of DKD is still unclear. We found that M1 macrophage-related markers were increased in diabetes mellitus (DM) mouse renal tissues with the development of DKD, and coculture of extracellular vesicles (EVs) from human serum albumin (HSA)-induced HK-2 cells with macrophages induced macrophage M1 polarization in the presence of lipopolysaccharide (LPS). Through a bioinformatic analysis, miR-199a-5p was selected and found to be increased in EVs from HSA-induced HK-2 cells and in urinary EVs from DM patients with macroalbuminuria. Tail-vein injection of DM mice with EVs from HSA-induced HK-2 cells induced kidney macrophage M1 polarization and accelerated the progression of DKD through miR-199a-5p. miR-199a-5p exerted its effect by targeting Klotho, and Klotho induced macrophage M2 polarization through the Toll-like receptor 4 (TLR4) pathway both in vivo and in vitro. In summary, miR-199a-5p from HSA-stimulated HK-2 cell-derived EVs induces M1 polarization by targeting the Klotho/TLR4 pathway and further accelerates the progression of DKD.
Topics: Albumins; Albuminuria; Animals; Biomarkers; Cell Communication; Cell Line; Epithelial Cells; Extracellular Vesicles; Fibrosis; Glucuronidase; Kidney Tubules; Klotho Proteins; Macrophage Activation; Macrophages; Mice; Models, Biological; Signal Transduction
PubMed: 31208912
DOI: 10.1016/j.ymthe.2019.05.019 -
Diabetologia Aug 2016Diabetic nephropathy is the main cause of end-stage renal failure in the Western world. In diabetes, metabolic and haemodynamic perturbations disrupt the integrity of... (Review)
Review
Diabetic nephropathy is the main cause of end-stage renal failure in the Western world. In diabetes, metabolic and haemodynamic perturbations disrupt the integrity of the glomerular filtration barrier, leading to ultrastructural alterations of the glomeruli, including podocyte foot process fusion and detachment, glomerular basement membrane thickening, reduced endothelial cell glycocalyx, and mesangial extracellular matrix accumulation and glomerulosclerosis, ultimately leading to albuminuria and end-stage renal disease. Many vascular growth factors, such as angiopoietins, are implicated in glomerular biology. In normal physiology angiopoietins regulate the function of the glomerular filtration barrier. When they are dysregulated, however, as they are in diabetes, they drive the cellular mechanisms that mediate diabetic glomerular pathology. Modulation of angiopoietins expression and signalling has been proposed as a tool to correct the cellular mechanisms involved in the pathophysiology of diabetic microvascular disease, such as retinopathy in humans. Future work might evaluate whether this novel therapeutic approach should be extended to diabetic kidney disease.
Topics: Albuminuria; Angiopoietins; Animals; Diabetic Nephropathies; Endothelial Cells; Humans; Kidney Glomerulus
PubMed: 27207083
DOI: 10.1007/s00125-016-3995-3 -
Clinical Journal of the American... Dec 2020Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).
RESULTS
Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; 0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.
CONCLUSIONS
Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.
Topics: Aged; Albuminuria; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Japan; Kidney; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pyrroles; Remission Induction; Risk Factors; Sulfones; Time Factors; Treatment Outcome
PubMed: 33239409
DOI: 10.2215/CJN.06870520 -
Journal of Clinical Hypertension... Jun 2011Albuminuria is an important risk marker for adverse cardiovascular (CV) and renal outcomes and mortality. The relationship between albuminuria and risk is continuous and... (Review)
Review
Albuminuria is an important risk marker for adverse cardiovascular (CV) and renal outcomes and mortality. The relationship between albuminuria and risk is continuous and linear, like that of blood pressure and cardiovascular risk. Evidence now supports increased risk even at levels traditionally considered within normal limits. In high-risk patients, routine annual screening can detect changes in urine albumin excretion and improve the timely identification of albuminuria, and therefore should be considered in patients with diabetes, hypertension, and chronic kidney disease. Preferred simple screening methods appropriate for use in the primary care setting include microalbumin-specific dipsticks and urinary albumin:creatinine ratio determination (from a spot urine sample). Cornerstones of albuminuria treatment include risk factor management, ongoing monitoring, and, in patients with hypertension, chronic kidney disease, or diabetes, the use of renin-angiotensin-aldosterone system (RAAS)-blocking agents. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have demonstrated utility in this regard; data from studies of direct renin inhibition are promising. The combined use of an ACE inhibitor and ARB was once considered a viable option for the treatment of albuminuria; however, results of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) raised important questions regarding the benefits and limitations of dual RAAS blockade. Ongoing studies should provide important insight into the effects of this approach on renal outcomes.
Topics: Albumins; Albuminuria; Algorithms; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Diabetes Mellitus; Diagnosis, Differential; Glomerular Filtration Rate; Humans; Hypertension; Mass Screening; Physicians, Primary Care; Primary Health Care; Renin-Angiotensin System; Risk Factors
PubMed: 21649844
DOI: 10.1111/j.1751-7176.2010.00424.x -
BMC Cardiovascular Disorders Nov 2022Studies suggest increased risk for an outcome in people with joint exposures that share common causal pathways. The objective of this study was to determine the risk of...
BACKGROUND
Studies suggest increased risk for an outcome in people with joint exposures that share common causal pathways. The objective of this study was to determine the risk of incident acute myocardial infarction (AMI) following exposure to both albuminuria and/or anxiety and depression symptoms.
METHODS
Participants who provided urine samples to the HUNT2 (1995-97) or HUNT3 (2007-2009) surveys were followed until the end of 2016. Albuminuria was measured by Albumin Creatine Ratio (ACR) and participants self-reported mood and anxiety symptoms on the Hospital Anxiety and Depression scale. We used Cox regression to estimate hazard ratios (HRs) for first incident AMI considering interaction between exposures and additive models to calculate the proportion of AMI that were attributable to the synergy of both exposures, adjusted for the Framingham variables.
RESULTS
Eleven thousand fourteen participants free of previous AMI were eligible for participation, with 1234 incident AMIs occurred during a mean 13.7 years of follow-up. For participants who had a healthier CVD risk profile, the HR for AMI of having both albuminuria (3-30 mg/mmol) and depression (≥8) was 2.62 (95% 1.12-6.05) compared with a HR 1.34 (95% CI 1.04-1.74) with raised ACR only (Likelihood Ratio-test 0.03). Adding anxiety (≥8) to albuminuria (3-30) tripled the risk (HR 3.32 95% CI 1.43-7.17). The additive models suggest that these risks are not higher than expected based on each risk factor alone.
CONCLUSIONS
This study indicate that the risk of AMI in persons with elevated albuminuria but with an otherwise healthy CVD profile might be amplified by anxiety and depression symptoms. The increased risk with joint risk factors is not higher than expected based on each risk factor alone, which indicate that the risk factors do not share causal pathways.
Topics: Humans; Albuminuria; Cohort Studies; Depression; Anxiety; Myocardial Infarction; Risk Factors
PubMed: 36348482
DOI: 10.1186/s12872-022-02921-1