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BioMed Research International 2021Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the... (Review)
Review
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting A1c < 7%, and <130/80 mmHg. Regression of albuminuria remains an important therapeutic goal. However, there are problems in diagnosis and treatment of nonproteinuric DN (NP-DN), which does not follow the classic pattern of DN. In fact, the prevalence of DN continues to increase, and additional therapy is needed to prevent or ameliorate the condition. In addition to conventional therapies, vitamin D receptor activators, incretin-related drugs, and therapies that target inflammation may also be promising for the prevention of DN progression. This review focuses on the role of inflammation and oxidative stress in the pathogenesis of DN, approaches to diagnosis in classic and NP-DN, and current and emerging therapeutic interventions.
Topics: Blood Glucose; Diabetic Nephropathies; Humans; Inflammation; Kidney; Oxidative Stress; Risk Factors
PubMed: 34307650
DOI: 10.1155/2021/1497449 -
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 -
Clinical Chemistry Mar 2022Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD).
METHODS
Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses.
RESULTS
One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR.
CONCLUSIONS
Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.
Topics: Albumins; Albuminuria; Body Mass Index; Creatinine; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Humans; Kidney; Mendelian Randomization Analysis; Obesity; Renal Insufficiency, Chronic
PubMed: 34922334
DOI: 10.1093/clinchem/hvab249 -
Frontiers in Endocrinology 2022Metabolic syndrome (MetS) includes visceral obesity, hyperglycemia, dyslipidemia, and hypertension. The prevalence of MetS is 20-25%, which is an important risk factor... (Review)
Review
Metabolic syndrome (MetS) includes visceral obesity, hyperglycemia, dyslipidemia, and hypertension. The prevalence of MetS is 20-25%, which is an important risk factor for chronic kidney disease (CKD). MetS causes effects on renal pathophysiology, including glomerular hyperfiltration, RAAS, microalbuminuria, profibrotic factors and podocyte injury. This review compares several criteria of MetS and analyzes their differences. MetS and the pathogenesis of CKD includes insulin resistance, obesity, dyslipidemia, inflammation, oxidative stress, and endothelial dysfunction. The intervention of MetS-related renal damage is the focus of this article and includes controlling body weight, hypertension, hyperglycemia, and hyperlipidemia, requiring all components to meet the criteria. In addition, interventions such as endoplasmic reticulum stress, oxidative stress, gut microbiota, body metabolism, appetite inhibition, podocyte apoptosis, and mesenchymal stem cells are reviewed.
Topics: Humans; Hyperglycemia; Hypertension; Kidney; Metabolic Syndrome; Renal Insufficiency, Chronic
PubMed: 35813613
DOI: 10.3389/fendo.2022.904001 -
Kidney International Jan 2021To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the... (Randomized Controlled Trial)
Randomized Controlled Trial
To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.
Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Japan
PubMed: 32891604
DOI: 10.1016/j.kint.2020.08.012 -
Current Cardiology Reviews 2020The globalization of the Western lifestyle has resulted in increase of diabetes mellitus, a complex, multifactorial disease. Diabetes mellitus is a condition often... (Review)
Review
The globalization of the Western lifestyle has resulted in increase of diabetes mellitus, a complex, multifactorial disease. Diabetes mellitus is a condition often related to the disorders of the cardiovascular system. It is well established that three quarters of diabetics, aged over 40, will die from cardiovascular disease and are more likely than non-diabetics to die from their first cardiovascular event. Therefore, it is of paramount importance to individualize treatment via risk stratification. Conditions that increase cardiovascular risk in people with diabetes include age more than 40 years, male gender, history of relative suffering from premature CHD, blood pressure and high LDL levels, presence of microalbuminuria, obstructive sleepapnea, erectile dysfunction and other conditions. Several models have been developed in order to assess cardiovascular risk in people with and without diabetes. Some of them have been proven to be inadequate while others are widely used for years. An emerging way of risk assessment in patients with diabetes mellitus is the use of biomarkers but a lot of research needs to be done in this field in order to have solid conclusions.
Topics: Adult; Biomarkers; Cardiovascular Diseases; Diabetes Complications; Female; Heart Disease Risk Factors; Humans; Male; Risk Assessment; Risk Factors
PubMed: 31713488
DOI: 10.2174/1573403X15666191111123622 -
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 -
Frontiers in Pharmacology 2021We aim to perform a systematic review and meta-analysis examining randomized controlled trials assessing the efficacy and safety of sacubitril/valsartan in patients on... (Review)
Review
We aim to perform a systematic review and meta-analysis examining randomized controlled trials assessing the efficacy and safety of sacubitril/valsartan in patients on renal outcomes, in comparison with the renin-angiotensin-aldosterone system inhibitor (RAASi). Eligible studies were retrieved on MEDLINE, EMBASE, and Cochrane until September 2021. The primary outcome was the incidence of renal impairment, which was defined as the composite of increases in serum creatinine by >0.3 mg/dl and/or a reduction in eGFR ≥25%, development of ESRD, or renal death. We pooled relative risks (RRs) with 95% confidence intervals (CIs) or the mean difference with 95% CIs for the variables. Our search yielded 10 randomized controlled trials with a total of 18,362 patients. Compared with RAASi treatment, patients treated with sacubitril/valsartan had lower incidence of composite renal impairment (10 studies, 18,362 patients, RR 0.84; 95% CI 0.72-0.96, = 0.01; = 22%), ESRD development (3 studies, 13,609 patients, RR 0.53; 95% CI 0.30-0.96, = 0.03; = 0%), drug discontinuation due to renal events (4 studies, 9,995 patients, RR 0.58; 95% CI 0.40-0.83, = 0.003; = 47%), severe hyperkalemia (6 studies, 16,653 patients, RR 0.80; 95% CI 0.68-0.93, = 0.01; = 25%) and a slower eGFR decline (4 studies, 13,608 patients, WMD 0.56; 95% CI 0.36-0.76, < 0.00001; = 65%). Subgroup analysis demonstrated that sacubitril/valsartan was associated with a lower incidence of renal impairment in patients with heart failure and preserved ejection fraction (HFpEF), but not in those with heart failure and reduced ejection fraction (HFrEF). The superior renal function preservation of sacubitril/valsartan treatment was not associated with different baseline eGFR levels and follow-up duration. There was a smaller increase in the change in the urine albumin-to-creatinine ratio (UACR) (3 studies, 9,114 patients, SMD 0.06; 95% CI 0.02-0.10, = 0.003; = 14%) with sacubitril/valsartan treatment. However, patients with heart failure appeared to have increased microalbuminuria, not patients without HF ( = 0.80 for interaction). Sacubitril/valsartan was associated with a lower incidence of composite renal impairment especially in patients with HFpEF, but higher microalbuminuria in patients with heart failure (both HFrEF and HFpEF) compared with RAASi. The lower incidence of severe hyperkalemia and drug discontinuation due to renal events in patients with sacubitril/valsartan treatment demonstrated its superior safety compared with RAASi.
PubMed: 34867310
DOI: 10.3389/fphar.2021.604017