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Diabetes, Obesity & Metabolism May 2019The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited,... (Meta-Analysis)
Meta-Analysis
Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis.
AIM
The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m .
MATERIALS AND METHODS
We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.
RESULTS
Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (-0.29%; 95% CI, -0.39 to -0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70-0.94) and heart failure (RR, 0.61; 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86; 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73 m /y; 95% CI, 0.78-1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes.
CONCLUSION
Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome
PubMed: 30697905
DOI: 10.1111/dom.13648 -
JAMA Feb 2015Because early-stage kidney disease is asymptomatic and is associated with both morbidity and mortality, laboratory measurements are required for its detection. (Review)
Review
IMPORTANCE
Because early-stage kidney disease is asymptomatic and is associated with both morbidity and mortality, laboratory measurements are required for its detection.
OBJECTIVE
To summarize evidence supporting the use of laboratory tests for glomerular filtration rate (GFR) and albuminuria to detect and stage acute kidney injury, acute kidney diseases and disorders, and chronic kidney disease in adults.
EVIDENCE REVIEW
We reviewed recent guidelines from various professional groups identified via the National Guideline Clearing House and author knowledge, and systematically searched MEDLINE for other sources of evidence for selected topics.
FINDINGS
The KDIGO (Kidney Disease Improving Global Outcomes) guidelines define and stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of GFR, measuring serum creatinine and reporting estimated GFR based on serum creatinine (eGFRcr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation is recommended. If confirmation of GFR is required because of conditions that affect serum creatinine independent of GFR (eg, extremes of muscle mass or diet), or interference with the assay, cystatin C should be measured and estimated GFR should be calculated and reported using cystatin C (eGFRcys) and serum creatinine (eGFRcr-cys) or GFR should be measured directly using a clearance procedure. Initial assessment of albuminuria includes measuring urine albumin and creatinine in an untimed spot urine collection and reporting albumin-to-creatinine ratio. If confirmation of albuminuria is required because of diurnal variation or conditions affecting creatinine excretion, such as extremes of muscle mass or diet, the albumin excretion rate should be measured from a timed urine collection.
CONCLUSIONS AND RELEVANCE
Detection and staging of acute and chronic kidney diseases can be relatively simple. Because of the morbidity and mortality associated with kidney disease, early diagnosis is important and should be pursued in at-risk populations.
Topics: Adult; Albuminuria; Creatinine; Cystatin C; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Practice Guidelines as Topic
PubMed: 25710660
DOI: 10.1001/jama.2015.0602 -
Advances in Therapy Jan 2021The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by glomerular filtration rate (GFR) and albuminuria to predict... (Review)
Review
INTRODUCTION
The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by glomerular filtration rate (GFR) and albuminuria to predict chronic kidney disease (CKD) prognosis. The aim of this systematic review was to explore the epidemiological burden of CKD stratified by the KDIGO 2012 categories.
METHODS
MEDLINE® and Embase were searched for observational studies of patients with CKD with results stratified according to the KDIGO 2012 classification. Investigated outcomes were prevalence, incidence, and risk factors and complications of CKD, including mortality.
RESULTS
The review included ten observational studies with 3033 to 46,949 participants, conducted in the USA, China, France, Italy and Spain. The most frequently reported outcome was the prevalence of CKD (GFR categories G3-5), ranging from 2% to 17%. Most participants were normoalbuminuric, with 0.4-3.2% macroalbuminuric, and most fell within the KDIGO 2012 low-risk or moderate-risk groups, with 0.9-5.6% in the high-risk and 0.3-4.8% in the very high-risk groups. Although scarce, data on the prevalence of comorbidities in CKD according to the KDIGO classification suggest that they increase with albuminuria severity.
CONCLUSIONS
Patients with CKD frequently have complications, but only a small proportion have severely increased albuminuria or fall within the KDIGO high-risk or very high-risk groups. These groups, however, are associated with the highest burden of disease, as comorbidities are more prevalent with increasing albuminuria severity. New studies framed by the KDIGO 2012 classification are needed to address key gaps in the understanding of CKD burden and outcomes.
Topics: Albuminuria; China; France; Glomerular Filtration Rate; Humans; Italy; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Spain
PubMed: 33231861
DOI: 10.1007/s12325-020-01568-8 -
Journal of the American Society of... Jan 2021Despite increasing incidence of CKD, no evidence-based lifestyle recommendations for CKD primary prevention apparently exist. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite increasing incidence of CKD, no evidence-based lifestyle recommendations for CKD primary prevention apparently exist.
METHODS
To evaluate the consistency of evidence associating modifiable lifestyle factors and CKD incidence, we searched MEDLINE, Embase, CINAHL, and references from eligible studies from database inception through June 2019. We included cohort studies of adults without CKD at baseline that reported lifestyle exposures (diet, physical activity, alcohol consumption, and tobacco smoking). The primary outcome was incident CKD (eGFR<60 ml/min per 1.73 m). Secondary outcomes included other CKD surrogate measures (RRT, GFR decline, and albuminuria).
RESULTS
We identified 104 studies of 2,755,719 participants with generally a low risk of bias. Higher dietary potassium intake associated with significantly decreased odds of CKD (odds ratio [OR], 0.78; 95% confidence interval [95% CI], 0.65 to 0.94), as did higher vegetable intake (OR, 0.79; 95% CI, 0.70 to 0.90); higher salt intake associated with significantly increased odds of CKD (OR, 1.21; 95% CI, 1.06 to 1.38). Being physically active versus sedentary associated with lower odds of CKD (OR, 0.82; 95% CI, 0.69 to 0.98). Current and former smokers had significantly increased odds of CKD compared with never smokers (OR, 1.18; 95% CI, 1.10 to 1.27). Compared with no consumption, moderate consumption of alcohol associated with reduced risk of CKD (relative risk, 0.86; 95% CI, 0.79 to 0.93). These associations were consistent, but evidence was predominantly of low to very low certainty. Results for secondary outcomes were consistent with the primary finding.
CONCLUSIONS
These findings identify modifiable lifestyle factors that consistently predict the incidence of CKD in the community and may inform both public health recommendations and clinical practice.
Topics: Alcohol Drinking; Diet; Disease Progression; Evidence-Based Medicine; Exercise; Glomerular Filtration Rate; Humans; Incidence; Kidney Failure, Chronic; Life Style; Observational Studies as Topic; Odds Ratio; Primary Prevention; Treatment Outcome
PubMed: 32868398
DOI: 10.1681/ASN.2020030384 -
Advances in Therapy Jan 2022Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment... (Review)
Review
Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment renin-angiotensin-aldosterone system (RAAS) inhibitors as the standard of care have scarcely met their primary endpoints until recently. This systematic literature review explored treatments evaluated in patients with CKD since 1990 to understand what contemporary data add to the treatment landscape. Eighty-nine clinical trials were identified that had enrolled patients with estimated glomerular filtration rate 13.9-102.8 mL/min/1.73 m and urinary albumin-to-creatinine ratio (UACR) 29.9-2911.0 mg/g, with (75.5%) and without (20.6%) type 2 diabetes (T2D). Clinically objective outcomes of kidney failure and all-cause mortality (ACM) were reported in 32 and 64 trials, respectively. Significant reductions (P < 0.05) in the risk of kidney failure were observed in seven trials: five small trials published before 2008 had evaluated the RAAS inhibitors losartan, benazepril, or ramipril in patients with (n = 751) or without (n = 84-436) T2D; two larger trials (n = 2152-2202) published onwards of 2019 had evaluated the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (in patients with T2D and UACR > 300-5000 mg/g) and dapagliflozin (in patients with or without T2D and UACR 200-5000 mg/g) added to a background of RAAS inhibition. Significant reductions in ACM were observed with dapagliflozin in the DAPA-CKD trial. Contemporary data therefore suggest that augmenting RAAS inhibitors with new drug classes has the potential to improve clinical outcomes in a broad range of patients with CKD.
Topics: Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 34881414
DOI: 10.1007/s12325-021-02006-z -
BMJ (Clinical Research Ed.) Sep 2021To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
OBJECTIVES
To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
DESIGN
Systematic review and external validation.
DATA SOURCES
PubMed and Embase.
ELIGIBILITY CRITERIA
Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes.
METHODS
Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell's C statistic).
RESULTS
41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons.
CONCLUSIONS
This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020192831.
Topics: Aged; Albuminuria; Calibration; Clinical Decision Rules; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Prognosis; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Assessment; Risk Factors
PubMed: 34583929
DOI: 10.1136/bmj.n2134 -
The Cochrane Database of Systematic... Sep 2018Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD make glucose-lowering challenging, increasing the risk of hypoglycaemia. Glucose-lowering agents have been mainly studied in people with near-normal kidney function. It is important to characterise existing knowledge of glucose-lowering agents in CKD to guide treatment.
OBJECTIVES
To examine the efficacy and safety of insulin and other pharmacological interventions for lowering glucose levels in people with diabetes and CKD.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All randomised controlled trials (RCTs) and quasi-RCTs looking at head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in people with diabetes and CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m) were eligible.
DATA COLLECTION AND ANALYSIS
Four authors independently assessed study eligibility, risk of bias, and quality of data and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Forty-four studies (128 records, 13,036 participants) were included. Nine studies compared sodium glucose co-transporter-2 (SGLT2) inhibitors to placebo; 13 studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; 2 studies compared glucagon-like peptide-1 (GLP-1) agonists to placebo; 8 studies compared glitazones to no glitazone treatment; 1 study compared glinide to no glinide treatment; and 4 studies compared different types, doses or modes of administration of insulin. In addition, 2 studies compared sitagliptin to glipizide; and 1 study compared each of sitagliptin to insulin, glitazars to pioglitazone, vildagliptin to sitagliptin, linagliptin to voglibose, and albiglutide to sitagliptin. Most studies had a high risk of bias due to funding and attrition bias, and an unclear risk of detection bias.Compared to placebo, SGLT2 inhibitors probably reduce HbA1c (7 studies, 1092 participants: MD -0.29%, -0.38 to -0.19 (-3.2 mmol/mol, -4.2 to -2.2); I = 0%), fasting blood glucose (FBG) (5 studies, 855 participants: MD -0.48 mmol/L, -0.78 to -0.19; I = 0%), systolic blood pressure (BP) (7 studies, 1198 participants: MD -4.68 mmHg, -6.69 to -2.68; I = 40%), diastolic BP (6 studies, 1142 participants: MD -1.72 mmHg, -2.77 to -0.66; I = 0%), heart failure (3 studies, 2519 participants: RR 0.59, 0.41 to 0.87; I = 0%), and hyperkalaemia (4 studies, 2788 participants: RR 0.58, 0.42 to 0.81; I = 0%); but probably increase genital infections (7 studies, 3086 participants: RR 2.50, 1.52 to 4.11; I = 0%), and creatinine (4 studies, 848 participants: MD 3.82 μmol/L, 1.45 to 6.19; I = 16%) (all effects of moderate certainty evidence). SGLT2 inhibitors may reduce weight (5 studies, 1029 participants: MD -1.41 kg, -1.8 to -1.02; I = 28%) and albuminuria (MD -8.14 mg/mmol creatinine, -14.51 to -1.77; I = 11%; low certainty evidence). SGLT2 inhibitors may have little or no effect on the risk of cardiovascular death, hypoglycaemia, acute kidney injury (AKI), and urinary tract infection (low certainty evidence). It is uncertain whether SGLT2 inhibitors have any effect on death, end-stage kidney disease (ESKD), hypovolaemia, fractures, diabetic ketoacidosis, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, DPP-4 inhibitors may reduce HbA1c (7 studies, 867 participants: MD -0.62%, -0.85 to -0.39 (-6.8 mmol/mol, -9.3 to -4.3); I = 59%) but may have little or no effect on FBG (low certainty evidence). DPP-4 inhibitors probably have little or no effect on cardiovascular death (2 studies, 5897 participants: RR 0.93, 0.77 to 1.11; I = 0%) and weight (2 studies, 210 participants: MD 0.16 kg, -0.58 to 0.90; I = 29%; moderate certainty evidence). Compared to placebo, DPP-4 inhibitors may have little or no effect on heart failure, upper respiratory tract infections, and liver impairment (low certainty evidence). Compared to placebo, it is uncertain whether DPP-4 inhibitors have any effect on eGFR, hypoglycaemia, pancreatitis, pancreatic cancer, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, GLP-1 agonists probably reduce HbA1c (7 studies, 867 participants: MD -0.53%, -1.01 to -0.06 (-5.8 mmol/mol, -11.0 to -0.7); I = 41%; moderate certainty evidence) and may reduce weight (low certainty evidence). GLP-1 agonists may have little or no effect on eGFR, hypoglycaemia, or discontinuation due to adverse effects (low certainty evidence). It is uncertain whether GLP-1 agonists reduce FBG, increase gastrointestinal symptoms, or affect the risk of pancreatitis (very low certainty evidence).Compared to placebo, it is uncertain whether glitazones have any effect on HbA1c, FBG, death, weight, and risk of hypoglycaemia (very low certainty evidence).Compared to glipizide, sitagliptin probably reduces hypoglycaemia (2 studies, 551 participants: RR 0.40, 0.23 to 0.69; I = 0%; moderate certainty evidence). Compared to glipizide, sitagliptin may have had little or no effect on HbA1c, FBG, weight, and eGFR (low certainty evidence). Compared to glipizide, it is uncertain if sitagliptin has any effect on death or discontinuation due to adverse effects (very low certainty).For types, dosages or modes of administration of insulin and other head-to-head comparisons only individual studies were available so no conclusions could be made.
AUTHORS' CONCLUSIONS
Evidence concerning the efficacy and safety of glucose-lowering agents in diabetes and CKD is limited. SGLT2 inhibitors and GLP-1 agonists are probably efficacious for glucose-lowering and DPP-4 inhibitors may be efficacious for glucose-lowering. Additionally, SGLT2 inhibitors probably reduce BP, heart failure, and hyperkalaemia but increase genital infections, and slightly increase creatinine. The safety profile for GLP-1 agonists is uncertain. No further conclusions could be made for the other classes of glucose-lowering agents including insulin. More high quality studies are required to help guide therapeutic choice for glucose-lowering in diabetes and CKD.
Topics: Cause of Death; Diabetes Mellitus; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glipizide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones
PubMed: 30246878
DOI: 10.1002/14651858.CD011798.pub2 -
Nutrients Dec 2021Non-alcoholic fatty liver disease (NAFLD) is an excessive accumulation of fat in the liver without alcohol abuse. It is linked to metabolic syndrome (MetS) and no...
BACKGROUND AND AIMS
Non-alcoholic fatty liver disease (NAFLD) is an excessive accumulation of fat in the liver without alcohol abuse. It is linked to metabolic syndrome (MetS) and no pharmacological treatment exists. This systematic review aims to assess evidence about the effect of Mediterranean lifestyle on the prevention and reversion of NAFLD.
METHODS
A systematic literature search was performed in MEDLINE via Pubmed. MeSH terms used were: non-alcoholic fatty liver disease [MeSH Major Topic] AND metabolic syndrome [MeSH Term] AND (Diet, Mediterranean [MeSH Term]) OR (Exercise [MeSH Term]). (PROSPERO ID: 2021 CRD42021289495).
RESULTS
Thirteen articles were selected and divided into two categories (four focused on Mediterranean diet and NAFLD and nine focused on Mediterranean diet, physical activity, and NAFLD). Information of clinical endpoints was based on NAFLD, as well as MetS, body mass index, fasting glycemia, obesity, cholesterol, triglycerides, transaminases, albuminuria, and hepatic steatosis, among others. All studies found beneficial associations between the clinical parameters of NAFLD/MetS and following a Mediterranean diet and regular physical activity.
CONCLUSIONS
An effective treatment that prevents, and even reverses, NAFLD is to adapt lifestyle to the Mediterranean one, based on a Mediterranean diet and regular physical activity.
Topics: Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Diet, Mediterranean; Exercise; Female; Humans; Life Style; Male; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Triglycerides; Young Adult
PubMed: 35010923
DOI: 10.3390/nu14010049 -
JAMA Network Open Oct 2023Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.
OBJECTIVE
To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.
DATA SOURCES
PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.
STUDY SELECTION
At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.
DATA EXTRACTION AND SYNTHESIS
Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.
MAIN OUTCOMES AND MEASURES
Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.
RESULTS
The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.
CONCLUSIONS AND RELEVANCE
The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.
Topics: Humans; Fetal Hemoglobin; alpha-Thalassemia; Anemia, Sickle Cell; Genotype; Genetic Variation
PubMed: 37851445
DOI: 10.1001/jamanetworkopen.2023.37484 -
Clinical and Experimental Nephrology Jan 2022To identify the association between albuminuria and dementia or cognitive impairment. (Meta-Analysis)
Meta-Analysis
BACKGROUND
To identify the association between albuminuria and dementia or cognitive impairment.
METHODS
The literature search was performed to identify relevant scientific studies through August 2019, including PubMed/Medline and EMBASE. For inclusion, the studies had to fulfil the following criteria: population-based cohort, case-control or cross-sectional studies; quantifying an association of albuminuria with cognitive impairment or dementia; and reported odds ratio (OR), and the corresponding 95% confidential interval (95% CI). Random effects model was used to yield pooled estimates.
RESULTS
A total of 16 studies (11 cohort studies and five cross-sectional studies) were included in the meta-analyses. Based on the fully adjusted estimates, albuminuria was associated with a significant higher risk of cognitive impairment or dementia. Furthermore, the same trend existed for cognitive impairment and dementia, respectively. In addition, both of Alzheimer's diseases (AD) and vascular dementia (VaD) were significantly associated with albuminuria.
CONCLUSION
Albuminuria was significantly associated with cognitive impairment and dementia. Corresponding to an earlier subclinical time-point in kidney disease progress, albuminuria may be a potential factor predicting the future occurrence of dementia.
Topics: Albuminuria; Alzheimer Disease; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Humans
PubMed: 34468878
DOI: 10.1007/s10157-021-02127-3