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Renoprotection with sodium-glucose cotransporter-2 inhibitors in children: Knowns and unknowns.
Jiang, B, Cheng, Z, Liu, F, Li, Q, Fu, H, Mao, J
Nephrology (Carlton, Vic.). 2022;(2):126-132
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent novel hypoglycemic drugs for the treatment of adult diabetes that have shown considerable potential for cardioprotection and renoprotection. This new drug can inhibit SGLT2 at the proximal tubule, increase glucosuria and natriuresis, and thus decreases the serum glucose level and blood pressure. Furthermore, the tubuloglomerular feedback activated by the natriuresis can decrease glomerular hyperfiltration, acknowledged as the main foundation of renoprotection. Several studies have confirmed the protective effects of SGLT2 inhibitors on the kidneys of adult diabetic patients and those with non-diabetic nephropathy; however, limited researches are seen in paediatric patients. In this review, we have summarized the mechanisms of action of SGLT2 inhibitors, the current experiences in adults, results of exploratory studies in children, and adverse events & obstacles of paediatric use. We further explore the potential and possible future research direction of SGLT2 inhibitors in paediatric diseases.
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Incidence and predictors of chronic kidney disease in type-II diabetes mellitus patients attending at the Amhara region referral hospitals, Ethiopia: A follow-up study.
Ahmed, MA, Ferede, YM, Takele, WW
PloS one. 2022;(1):e0263138
Abstract
BACKGROUND Chronic kidney disease (CKD) is the severest form of kidney disease characterized by poor filtration. The magnitude of chronic kidney disease is trending upward in the last few years linked with the rapidly escalating cases of non-communicable chronic diseases, particularly diabetes mellitus. However, little is known about when this problem may occur, the incidence as well as predictors of chronic kidney disease among type-II diabetes mellitus patients. Thus, this study was conducted to determine the incidence, time to the occurrence, and predictors of chronic kidney disease in type-II diabetic patients attending the Amhara region referral hospitals, Ethiopia. METHODS A retrospective follow-up study was conducted involving 415 participants with type-II diabetes mellitus that enrolled in the chronic follow-up from 2012 to 2017. Multivariable shared Frailty Weibull (Gamma) survival model was employed considering the hospitals as a clustering variable. Model fitness was checked by both the Akaike information criteria (AIC) and log-likelihood. Factors having a p-value of ≤0.2 in the bi-variable analysis were considered to enter the multivariable model. Variables that had a p-value of <0.05 with its corresponding 95% confidence level were deemed to be significant predictors of chronic kidney disease. RESULTS The overall cumulative incidence of chronic kidney disease was 10.8% [95%; CI: 7.7-14.0%] with a median occurrence time of 5 years. The annual incidence rate was 193/10,000 [95%; CI: 144.28-258.78]. Having cardiovascular disease/s [AHR = 3.82; 95%CI: 1.4470-10.1023] and hypercholesterolemia [AHR = 3.31; 95% CI: 1.3323-8.2703] were predictors of chronic kidney disease. CONCLUSION One out of every ten diabetic patients experienced chronic kidney disease. The median time to develop chronic kidney disease was five years. Hypercholesterolemia and cardiovascular diseases have escalated the hazard of developing CKD. Thus, health promotion and education of diabetic patients to optimize cholesterol levels and prevent cardiovascular disease is recommended to limit the occurrence of this life-threatening disease.
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Effects of physical activity on the progression of diabetic nephropathy: a meta-analysis.
Cai, Z, Yang, Y, Zhang, J
Bioscience reports. 2021;(1)
Abstract
BACKGROUND Diabetic nephropathy (DN) is an important microvascular complication of diabetes. Physical activity (PA) is part of a healthy lifestyle for diabetic patients; however, the role of PA in DN has not been clarified. Our aim was to conduct a meta-analysis to explore the association between PA and DN risk. METHODS PubMed, Embase, Cochrane Library and Web of Science were systematically searched for articles examining PA in diabetic patients and its effect on renal function. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. The study protocol is registered with PROSPERO (CRD42020191379). RESULTS A total of 38991 participants were identified from 18 studies. The results indicated that PA was associated with increases in the glomerular filtration rate (SMD = 0.01, 95% CI = [0.02-0.17]) and decreases in the urinary albumin creatinine ratio (SMD = -0.53, 95% CI: -0.72 to -0.34), rate of microalbuminuria (OR = 0.61, 95% CI = [0.46-0.81]), rate of acute kidney injury (OR = 0.02, 95% CI = [0.01-0.04]), rate of renal failure (OR = 0.71, 95% CI = [0.52-0.97]) and risk of DN in patients with Type 1 diabetes (OR = 0.67, 95% CI = [0.51-0.89]). CONCLUSIONS This meta-analysis indicated that PA is effective for improving DN and slowing its progression; however, more high-quality randomized controlled trials are required on this topic.
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Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors.
Scholtes, RA, van Baar, MJB, Kok, MD, Bjornstad, P, Cherney, DZI, Joles, JA, van Raalte, DH
Nephrology (Carlton, Vic.). 2021;(5):377-390
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Abstract
Diabetic kidney disease remains the leading cause of end-stage kidney disease and a major risk factor for cardiovascular disease. Large cardiovascular outcome trials and dedicated kidney trials have shown that sodium-glucose cotransporter (SGLT)2 inhibitors reduce cardiovascular morbidity and mortality and attenuate hard renal outcomes in patients with type 2 diabetes (T2D). Underlying mechanisms explaining these renal benefits may be mediated by decreased glomerular hypertension, possibly by vasodilation of the post-glomerular arteriole. People with T2D often receive several different drugs, some of which could also impact the renal vasculature, and could therefore modify both renal efficacy and safety of SGLT2 inhibition. The most commonly prescribed drugs that could interact with SGLT2 inhibitors on renal haemodynamic function include renin-angiotensin system inhibitors, calcium channel blockers and diuretics. Herein, we review the effects of these drugs on renal haemodynamic function in people with T2D and focus on studies that measured glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) with gold-standard techniques. In addition, we posit, based on these observations, potential interactions with SGLT2 inhibitors with an emphasis on efficacy and safety.
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Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease.
Shaffner, J, Chen, B, Malhotra, DK, Dworkin, LD, Gong, R
Frontiers in endocrinology. 2021;:749010
Abstract
As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.
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Performance of prediction models for nephropathy in people with type 2 diabetes: systematic review and external validation study.
Slieker, RC, van der Heijden, AAWA, Siddiqui, MK, Langendoen-Gort, M, Nijpels, G, Herings, R, Feenstra, TL, Moons, KGM, Bell, S, Elders, PJ, et al
BMJ (Clinical research ed.). 2021;:n2134
Abstract
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.
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The predictive value of diabetic retinopathy on subsequent diabetic nephropathy in patients with type 2 diabetes: a systematic review and meta-analysis of prospective studies.
Li, Y, Su, X, Ye, Q, Guo, X, Xu, B, Guan, T, Chen, A
Renal failure. 2021;(1):231-240
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This systematic review and meta-analysis aimed to assess the predictive value of diabetic retinopathy (DR) on further diabetic nephropathy (DN) risk in patients with type 2 diabetes (T2D) based on the prospective cohort studies. PubMed, Embase, and the Cochrane Library were systematically searched for eligible prospective cohort studies through March 2020. The predictive value of DR was assessed using sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) through the bivariate generalized linear mixed model and the random-effects model. Ten prospective cohort studies recruited 635 patients with T2D. The pooled sensitivity and specificity of DR for predicted DN were noted to be 0.64 (95% CI, 0.54-0.73) and 0.77 (95% CI, 0.60-0.88), respectively. The pooled PLR and NLR of DR for predicted DN were 2.72 (95% CI, 1.42-5.19) and 0.47 (95% CI, 0.33-0.67), respectively. The summary DOR for the relationship between DR and subsequent DN for T2D patients was 5.53 (95% CI, 2.00-15.30), and the AUC of DR for predicted DN was 0.73 (95% CI, 0.69-0.77). This study found significant associations between DR and subsequent DN risk for patients with T2D. Moreover, the predictive value of DR on subsequent DN risk was relatively lower.
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SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.
Tuttle, KR, Brosius, FC, Cavender, MA, Fioretto, P, Fowler, KJ, Heerspink, HJL, Manley, T, McGuire, DK, Molitch, ME, Mottl, AK, et al
Diabetes. 2021;(1):1-16
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Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.
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Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.
Koomen, JV, Stevens, J, Bakris, G, Correa-Rotter, R, Hou, FF, Kitzman, DW, Kohan, DE, Makino, H, McMurray, JJV, Parving, HH, et al
Clinical pharmacology and therapeutics. 2021;(6):1631-1638
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Abstract
Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
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High urinary glucose is associated with improved renal prognosis in patients with diabetes mellitus.
Itano, Y, Sobajima, H, Ohashi, N, Shibata, T, Fujiya, A, Nagata, T, Ando, M, Imaizumi, T, Kubo, Y, Ozeki, T, et al
Journal of diabetes investigation. 2021;(6):998-1006
Abstract
AIMS/INTRODUCTION The relationship between renal function and urinary glucose is poorly understood in diabetes patients who are not using sodium-glucose cotransporter 2 inhibitors. This study aimed to investigate the association of urinary glucose excretion with renal function prognosis in such patients. MATERIALS AND METHODS This retrospective cohort study included 1,172 patients with type 1 or 2 diabetes mellitus. Patients were recruited and data were collected between 1 January 2007 and 31 December 2011; follow-up data were collected until 30 June 2015. The primary outcome was set as a 30% decline in estimated glomerular filtration rate relative to baseline. The relationship between this outcome and urinary glucose was investigated using Cox proportional hazards model. For analysis, patients were categorized into two groups: urinary glucose <5 g/day or ≥5 g/day. Interaction terms were analyzed. RESULTS Multivariate analysis showed that the prognosis of renal function was significantly better in patients with high urinary glucose (≥5 g/day; adjusted hazard ratio 0.58, 95% confidence interval 0.35-0.96; P = 0.034). Significant interactions were observed between high urinary glucose and male sex (hazard ratio 0.33, 95% confidence interval 0.14-0.74; P = 0.007), and between high urinary glucose and longer duration of diabetes (≥10 years; hazard ratio 0.25, 95% confidence interval 0.11-0.58; P = 0.001). CONCLUSIONS The present study suggests that high urinary glucose is associated with prognosis in diabetes patients not taking sodium-glucose cotransporter 2 inhibitors. Measurement of 24-h urinary glucose excretion might have clinical utility for predicting renal prognosis.