Review of potential biomarkers of inflammation and kidney injury in diabetic kidney disease.

Diabetic kidney disease is expected to increase rapidly over the coming decades with rising prevalence of diabetes worldwide. Current measures of kidney function based on albuminuria and estimated glomerular filtration rate do not accurately stratify and predict individuals at risk of declining kidney function in diabetes. As a result, recent attention has turned towards identifying and assessing the utility of biomarkers in diabetic kidney disease. This review explores the current literature on biomarkers of inflammation and kidney injury focussing on studies of single or multiple biomarkers between January 2014 and February 2020. Multiple serum and urine biomarkers of inflammation and kidney injury have demonstrated significant association with the development and progression of diabetic kidney disease. Of the inflammatory biomarkers, tumour necrosis factor receptor-1 and -2 were frequently studied and appear to hold most promise as markers of diabetic kidney disease. With regards to kidney injury biomarkers, studies have largely targeted markers of tubular injury of which kidney injury molecule-1, beta-2-microglobulin and neutrophil gelatinase-associated lipocalin emerged as potential candidates. Finally, the use of a small panel of selective biomarkers appears to perform just as well as a panel of multiple biomarkers for predicting kidney function decline.

Role of the adaptive immune system in diabetic kidney disease.

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end-stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro-inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor-α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Efficacy of Flash Glucose Monitoring in Type 1 and Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Objective: Flash glucose monitoring (FlashGM) is a sensor-based technology that displays glucose readings and trends to people with diabetes. In this meta-analysis, we assessed the effect of FlashGM on glycaemic outcomes including HbA1c, time in range, frequency of hypoglycaemic episodes and time in hypo/hyperglycaemia compared to self-monitoring of blood glucose, using data from randomised controlled trials. Methods: A systematic search was conducted on MEDLINE, EMBASE and CENTRAL for articles published between 2014 and 2021. We selected randomised controlled trials comparing flash glucose monitoring to self-monitoring of blood glucose that reported change in HbA1c and at least one other glycaemic outcome in adults with type 1 or type 2 diabetes. Two independent reviewers extracted data from each study using a piloted form. Meta-analyses using a random-effects model was conducted to obtain a pooled estimate of the treatment effect. Heterogeneity was assessed using forest plots and the I2 statistic. Results: We identified 5 randomised controlled trials lasting 10 - 24 weeks and involving 719 participants. Flash glucose monitoring did not lead to a significant reduction in HbA1c. However, it resulted in increased time in range (mean difference 1.16 hr, 95% CI 0.13 to 2.19, I2 = 71.7%) and decreased frequency of hypoglycaemic episodes (mean difference -0.28 episodes per 24 hours, 95% CI -0.53 to -0.04, I2 = 71.4%). Conclusions: Flash glucose monitoring did not lead to a significant reduction in HbA1c compared to self-monitoring of blood glucose, however, it improved glycaemic management through increased time in range and decreased frequency of hypoglycaemic episodes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42020165688).

Performance of 4 Creatinine-based Equations in Assessing Glomerular Filtration Rate in Adults with Diabetes.

AIMS: To evaluate diagnostic performance of glomerular filtration rate (GFR) estimated by modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI), full age spectrum (FAS), and revised Lund-Malmö (r-LM) equations in adults with diabetes. METHODS: Individuals were included in this cross-sectional study if they had at least 1 measurement of technetium-99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) GFR (mGFR) and serum creatinine (1487 patients with 2703 measures). GFR calculated by estimation equations was compared with mGFR. Diagnostic performance was assessed using concordance correlation coefficient (CCC), bias, precision, accuracy, reduced major axis regression (RMAR), and Bland-Altman plot. Analysis was repeated in subgroups based on sex, diabetes type, Hemoglobin A1C, and GFR level. RESULTS: Of all patients, 1189 (86%) had type 2 diabetes. Mean mGFR, MDRD, CKD-EPI, FAS, and revised Lund-Malmö eGFR were 66, 72, 74, 71, and 67 mL/min/1.73m2, respectively. Overall, the r-LM had the highest CCC (0.83), lowest bias (-1.4 mL/min/1.73 m2), highest precision (16.2 mL/min/1.73 m2), and highest accuracy (P10 = 39%). The RMAR (slope, intercept) in r-LM, FAS, MDRD, and CKD-EPI was 1.18, -13.35; 0.97, -2.9; 1, -6.4, and 1.04, -11.3, respectively. The Bland-Altman plot showed that r-LM had the lowest mean difference and the narrowest 95% limit of agreement (-1.0, 54.1 mL/min/1.73 m2), while mean difference was more than 5-fold higher in FAS, MDRD, and CKD-EPI (-5.2, -6.3, and -8.2, respectively). CONCLUSIONS: In adults with diabetes the revised Lund-Malmö performs better than MDRD, CKD-EPI, and FAS in calculating point estimates of GFR.

Long-term effectiveness of a lifestyle intervention on the prevention of type 2 diabetes in a middle-income country.

This study aims to assess the effects of a community-based lifestyle intervention program on the incidence of type 2 diabetes (T2D). For this purpose, three communities in Tehran were chosen; one community received a face-to-face educational session embedded in a long-term community-wide lifestyle intervention aimed at supporting lifestyle changes. We followed up 9,204 participants (control: 5,739, intervention: 3,465) triennially from 1999 to 2015 (Waves 1-5). After a median follow-up of 3.5 years (wave 2), the risk of T2D was 30% lower in the intervention community as compared with two control communities by (Hazard-ratio: 0.70 [95% CI 0.53; 0.91]); however, the difference was not statistically significant in the following waves. After a median follow-up of 11.9 years (wave 5), there was a non-significant 6% reduction in the incidence of T2D in the intervention group as compared to the control group (Hazard-ratio: 0.94 [0.81, 1.08]). Moreover, after 11.9 years of follow-up, the intervention significantly improved the diet quality measured by the Dietary Approaches to Stop Hypertension concordance (DASH) score. Mean difference in DASH score in the intervention group versus control group was 0.2 [95% CI 0.1; 0.3]. In conclusion, the intervention prevented T2D by 30% in the short-term (3.5 years) but not long-term; however, effects on improvement of the diet maintained in the long-term.Registration: This study is registered at IRCT, a WHO primary registry ( https://irct.ir ). The registration date 39 is 2008-10-29 and the IRCT registration number is IRCT138705301058N1.

Diagnostic performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at estimating glomerular filtration rate in adults with diabetes mellitus: a systematic review and meta-analysis protocol.

INTRODUCTION: Timely detection leading to the implementation of reno-protective measures reduces the progression of diabetic kidney disease. Estimated glomerular filtration rate (eGFR) is a major surrogate of kidney function. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation is a tool to estimate GFR. This protocol outlines a systematic-review, assessing the diagnostic accuracy of the CKD-EPI equation in adults with diabetes. METHODS AND ANALYSIS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials and grey literature will be searched for publications in English, Farsi, Dutch and Chinese from 2009 (when CKD-EPI was first introduced) to January 2019. Bridging searches will be conducted to capture literature published from January 2019 until final review publication. The inclusion criteria will be (1) study participants with diabetes; (2) age ≥18 years; (3) creatinine-based CKD-EPI eGFR as index test; (4) measured GFR using the clearance/plasma disappearance of inulin, iohexol, iothalamate, diethylenetriamine-pentaacetic acid (DTPA) or chromium labelled ethylenediaminetetraacetic acid (Cr-EDTA) as reference test; (5) report of the diagnostic accuracy of the index test. Exclusion criteria will be participants with renal transplant, chronic use of corticosteroids, chronic inflammatory diseases, pregnancy, non-diabetes related kidney disease, thalassaemia, heart failure, pregnancy and potential kidney donors as well as critically ill patients. Screening, eligibility check, risk of bias assessment and data extraction will be carried out by two independent reviewers. Any discrepancies will be discussed, and third-party opinion will be sought. The risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A quantitative synthesis of the aggregated-data will be used if the included studies are homogenous. ETHICS AND DISSEMINATION: No ethics approval is required. The outcome will be published in a peer-reviewed journal. The results will help researchers and clinicians evaluate the diagnostic accuracy of the creatinine-based CKD-EPI eGFR in adults with diabetes. PROSPERO REGISTRATION NUMBER: CRD42018108776.

Long-Term Effectiveness of a Lifestyle Intervention: A Pragmatic Community Trial to Prevent Metabolic Syndrome.

INTRODUCTION: The purpose of this study is to evaluate the long-term effectiveness of a community-based lifestyle education on primary prevention of metabolic syndrome in a middle-income country. STUDY DESIGN: This study followed 3,180 individuals free of metabolic syndrome who were under the coverage of three health centers in Tehran from 1999 until 2015. They were undergoing triennial examinations resulting in four re-exams. People in one of three areas received interventions consisting of family-, school-, and community-based educational programs, including a face-to-face educational session at baseline. Data were analyzed considering the incidence of metabolic syndrome at each re-exam and also repeated-measure analysis including all re-exams together. Weighting was considered to correct selection bias because of loss to follow-up. Data were analyzed in 2017. RESULTS: After 3 years, 149 of 852 participants in the intervention and 471 of 2,328 people in control area developed metabolic syndrome at first re-exam resulting in a RR of 0.78 (95% CI=0.67, 0.92). The difference between groups remained unchanged up to the 6-year follow-up (RR=0.79, 95% CI=0.66, 0.93, at second re-exam), but disappeared during the third and fourth re-exams (RR=1.04, 95% CI=0.91, 1.18 and RR=1.03, 95% CI=0.91, 1.16, respectively). Marginal models for longitudinal data showed a significant interaction between intervention and time of re-exams. Further analyses showed that the effect of the intervention might have been rooted in improvement of lipid profile and glucose level. CONCLUSIONS: In a middle-income country, face-to-face educational sessions followed by a long-term maintenance community-level educational program could reduce the risk of metabolic syndrome for up to 6 years. A booster face-to-face session is recommended to retain this preventive effect. TRIAL REGISTRATION: This study is registered at Iran Registry for Clinical Trials (http://irct.ir) IRCT138705301058N1.

World Bank Income Group, Health Expenditure or Cardiometabolic Risk Factors? A Further Explanation of the Wide Gap in Cardiometabolic Mortality Between Worldwide Countries: An Ecological Study.

BACKGROUND: For addressing the burden of non-communicable diseases and policymaking, the world health organization uses World Bank income group to classify countries. This calcification method might not be optimal. This study aimed to investigate the role of World Bank income group, health expenditure, and cardiometabolic risk factors of countries in explaining the gap between their cardiometabolic mortality. METHODS: In total, 190 countries were categorized into four income groups according to the World Bank definition. The energy consumption, health expenditure, and data of sex-specified age-standardized prevalence of obesity, hypercholesterolemia, hypertension, diabetes, smoking, and physical inactivity in 2008 and cardiometabolic mortality in 2012 were used. Multivariable-adjusted mixed-effect linear regression models were applied to relate country-level predictors to their mortality outcomes. RESULTS: While the lowest cardiometabolic mortality was recorded in high-income countries in both genders, the highest rates were recorded in the low-income category for women and in low and middle-income for men. Countries had lower cardiometabolic mortality for women compared to men; however, such a difference was not shown in low-income countries. World Bank income group of countries, per se, explained one-third of the variation in their mortality outcomes while adding health expenditure, energy consumption, and cardiometabolic risk factors increased the explanatory power of the model considerably. Moreover, the more the health expenditure, the weaker the association of prevalence of hypertension with cardiometabolic mortality. CONCLUSIONS: Adding countries' health expenditure and/or the prevalence of risk factors to their World Bank income group may contribute to the better explanation of the gap between them in cardiometabolic mortality.

Optimal cut-points of different anthropometric indices and their joint effect in prediction of type 2 diabetes: results of a cohort study.

BACKGROUND: To determine the anthropometric indices that would predict type 2 diabetes (T2D) and delineate their optimal cut-points. METHODS: In a cohort study, 7017 Iranian adults, aged 20-60 years, free of T2D at baseline were investigated. Using Cox proportional hazard models, hazard ratios (HRs) for incident T2D per 1 SD change in body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR), waist to hip ratio (WHR), and hip circumference (HC) were calculated. The area under the receiver operating characteristics (ROC) curves (AUC) was calculated to compare the discriminative power of anthropometric variables for incident T2D. Cut-points of each index were estimated by the maximum value of Youden's index and fixing the sensitivity at 75%. Using the derived cut-points, joint effects of BMI and other obesity indices on T2D hazard were assessed. RESULTS: During a median follow-up of 12 years, 354 men, and 490 women developed T2D. In both sexes, 1 SD increase in anthropometric variables showed significant association with incident T2D, except for HC in multivariate adjusted model in men. In both sexes, WHtR had the highest discriminatory power while HC had the lowest. The derived cut-points for BMI, WC, WHtR, WHR, and HC were 25.56 kg/m2, 89 cm, 0.52, 0.91, and 96 cm in men and 27.12 kg/m2, 87 cm, 0.56, 0.83, and 103 cm in women, respectively. Assessing joint effects of BMI and each of the obesity measures in the prediction of incident T2D showed that among both sexes, combined high values of obesity indices increase the specificity for the price of reduced sensitivity and positive predictive value. CONCLUSIONS: Our derived cut-points differ between both sexes and are different from other ethnicities.

Impact Of Hypertension versus Diabetes on Cardiovascular and All-cause Mortality in Iranian Older Adults: Results of 14 Years of Follow-up.

To evaluate the joint effect of hypertension (HTN) and diabetes (DM) on coronary heart disease (CHD), and stroke event, all-cause, and cardiovascular disease (CVD) mortality in Middle Eastern older adults, 2747 people (1436 women) aged ≥ 50 years, free of CVD at baseline, were categorized into four groups (HTN-/DM-, HTN+/DM-, HTN-/DM+, HTN+/DM+). Multivariate Cox proportional hazard models were run for different outcomes. To compare the impact of HTN versus DM, HTN+/DM- was considered as reference. In a median of 13.9 years, incidence rate of CHD, and stroke event, all-cause and CVD mortality in total population were 19.0, 4.7, 13.5, and 6.4 per 1000 person-years, respectively. The multivariate sex-adjusted hazard ratios (HRs) of HTN-/DM+ for CHD, stroke, all-cause mortality and CVD mortality were 1.19 (confidence interval (CI): 0.9-1.57), 1.07 (CI: 0.63-1.82), 1.62 (CI: 1.2-2.18), and 1.28 (CI: 0.83-1.97); the corresponding HRs for HTN+/DM+ were 1.96 (CI: 1.57-2.46), 1.66 (CI: 1.1-2.52), 2.32 (CI: 1.8-2.98), and 2.6 (CI: 1.85-3.65) respectively. The associations between HTN/DM status with stroke incidence and all-cause mortality were stronger among men than in women (P for interaction <0.05). Compared to HTN+/DM-, HTN-/DM+ increases all-cause mortality by 62%, however, they are not considerably different regarding CHD, stroke incidence and CVD mortality.

Trends in cardiovascular disease risk factors in people with and without diabetes mellitus: a Middle Eastern cohort study.

AIMS/HYPOTHESIS: To investigate secular trends in cardiovascular disease (CVD) risk factors during a decade of follow-up in a Middle Eastern cohort, and to compare observed trends between diabetic and non-diabetic populations. METHODS: In a population of 6181 participants (2622 males and 3559 females), diabetes status and CVD risk factors were evaluated in 4 study phases from 1999-2011. 1045 subjects had type 2 diabetes mellitus at baseline and 5136 participants were diabetes-free. To examine the trends of CVD risk factors, generalized estimation equation models were constructed. The interaction between the diabetes status and each phase of the study was checked in a separate model. RESULTS: During the follow-up period diabetic females significantly gained better control of their blood pressure, serum low density lipoprotein cholesterol and general and central obesity measures compared to non-diabetic counterparts, although 60% of them had high BP and 64% had high serum LDL-C levels till the end of the study. Diabetic males however, experienced significantly better control on their serum LDL-C and general and central obesity measures compared to their non-diabetic controls; but 24% of them were still smoker, 63% had high BP and 60% had high serum LDL-C levels at the end of the follow-up (all Ps interaction <0.05). Use of lipid-lowering and antihypertensive medications increased consistently in both diabetic and non-diabetic populations. CONCLUSIONS/INTERPRETATION: Although CVD risk factors have been controlled to some extent among diabetic population in Iran, still high numbers of people with diabetes have uncontrolled CVD risk factors that prompt more attention.