Cardiorenal Complications Research Articles

Current gaps in management and timely referral of cardiorenal complications among people with type 2 diabetes mellitus in the Middle East and African countries: Expert recommendations.

The upsurge of type 2 diabetes mellitus is a major public health concern in the Middle East and North Africa (MENA) and Africa (AFR) region, with cardiorenal complications (CRCs) being the predominant cause of premature morbidity and mortality. High prevalence of cardiometabolic risk factors, lack of awareness among patients and physicians, deficient infrastructure, and economic constraints lead to a cascade of CRCs at a significantly earlier age in MENA and AFR. In this review, we present consensus recommendations by experts in MENA and AFR, highlighting region‐specific challenges and potential solutions for management of CRCs. Health professionals who understand sociocultural barriers can significantly increase patient awareness and encourage health‐seeking behavior through simple educational tools. Increasing physician knowledge on early identification of CRCs and personalized treatment based on risk stratification, alongside optimum glycemic control, can mitigate therapeutic inertia. Early diagnosis of high‐risk people with regular and systematic monitoring of cardiorenal parameters, development of region‐specific care pathways for timely referral to specialists, followed by guideline‐recommended care with novel antidiabetics are imperative. Adherence to guideline‐recommended care can catalyze utilization of sodium glucose cotransporter 2 inhibitors and glucagon‐like peptide 1 receptor agonists with demonstrated cardiorenal benefits—thus paving the way for overcoming care gaps in a cost‐effective manner. Leveraging digital technology like electronic medical records can help generate real‐world data and provide insights on voids in adoption of newer antidiabetic medications. A patient‐centric approach, collaborative care among physicians from different specialties, alongside involvement of policy makers are key for improving patient outcomes and quality of care in MENA and AFR.

IDF21-0197 Take CaRe of Me Programme: Gaps in early diagnosis of cardiorenal complications in type 2 diabetes from 6 countries

IDF21-0197 Take CaRe of Me Programme: Gaps in early diagnosis of cardiorenal complications in type 2 diabetes from 6 countries

IDF21-0122 Cardio-renal complications in type 2 diabetes at the first add-on to metformin: an international retrospective study

Background: Results of clinical trials with cardiovascular (CV) and renal outcomes led to a significant change of the treatment guidelines in type 2 diabetes (T2D). Medications with proven cardio-renal benefit (sodium-glucose co-transporter 2 inhibitors, SGLT2i and glucagon-like peptide 1 receptor agonists, GLP-1 RA) are now recommended as first add-on to metformin in subjects with indicators of high-risk (IHR) or established atherosclerotic CV disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review.

Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The ‘SGLT2i Prescribing Tool for T2DM Management’, previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01228-w.

Diabetic Cardiomyopathy and Nephropathy: Lessons from The Hong Kong Diabetes Register

Diabetes is a major cause of end-stage renal disease in Hong Kong and globally. The burden of diabetic kidney disease continues to rise despite efforts in combating obesity and diabetes. Furthermore, there is changing epidemiology of diabetic kidney disease (DKD) with increasing proportion with reduced eGFR as opposed to albuminuria. DKD is closely linked to hospitalization with heart failure, another important complication of diabetes. While multiple factors including hypertension, coronary heart disease, hyperlipidemia, inflammation and arrhythmia contribute to the development of congestive heart failure in diabetes, it is increasingly recognized that cardiac remodeling can occur in the absence of coronary heart disease, giving rise to diabetic cardiomyopathy. Using the Hong Kong Diabetes Register, a prospective cohort of Chinese patients with type 2 diabetes, we have developed risk equations for predicting incident heart failure in diabetes, as well as examined the interaction between cardio-renal outcomes. Recent work utilizing the multicenter Hong Kong Diabetes Biobank has highlighted heterogeneity in terms of cardiorenal risks according to subphenotype of DKD. While there has been significant reduction in cardiovascular events among patients with diabetes over last 2 decades, rates of renal complications remain substantial. The introduction of newer agents, as well as structured programs to improve multiple cardiometabolic risk factors, should help to reduce the burden of cardiorenal complications in diabetes. Diabetes is a major cause of end-stage renal disease in Hong Kong and globally. The burden of diabetic kidney disease continues to rise despite efforts in combating obesity and diabetes. Furthermore, there is changing epidemiology of diabetic kidney disease (DKD) with increasing proportion with reduced eGFR as opposed to albuminuria. DKD is closely linked to hospitalization with heart failure, another important complication of diabetes. While multiple factors including hypertension, coronary heart disease, hyperlipidemia, inflammation and arrhythmia contribute to the development of congestive heart failure in diabetes, it is increasingly recognized that cardiac remodeling can occur in the absence of coronary heart disease, giving rise to diabetic cardiomyopathy. Using the Hong Kong Diabetes Register, a prospective cohort of Chinese patients with type 2 diabetes, we have developed risk equations for predicting incident heart failure in diabetes, as well as examined the interaction between cardio-renal outcomes. Recent work utilizing the multicenter Hong Kong Diabetes Biobank has highlighted heterogeneity in terms of cardiorenal risks according to subphenotype of DKD. While there has been significant reduction in cardiovascular events among patients with diabetes over last 2 decades, rates of renal complications remain substantial. The introduction of newer agents, as well as structured programs to improve multiple cardiometabolic risk factors, should help to reduce the burden of cardiorenal complications in diabetes.

Are Our Type 2 Diabetes Patients Sufficiently Protected from Cardiorenal Complications?

Are Our Type 2 Diabetes Patients Sufficiently Protected from Cardiorenal Complications?

Cardio-renal outcomes and the direct medical cost of type 2 diabetes patients treated with sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based cohort study

AimsTo compare cardio-renal outcomes and incurred direct medical costs of patients initiating sodium glucose cotransporter-2 inhibitors (SGLT2i) versus glucagon-like peptide-1 receptor agonists (GLP-1RA). MethodsA population-based cohort of patients with type 2 diabetes was identified from Hong Kong Hospital Authority. Patients who were free from cardiovascular and end-stage renal diseases at baseline, and newly treated with SGLT2i (n = 2,541) or GLP-1RA (n = 303), were included. Risks of developing cardio-renal complications, incurred direct medical costs, and changes in clinical parameters were assessed between groups. ResultsOver a median follow-up of 12.5 months in SGLT2i group and 25.5 months in GLP-1RA group, SGLT2i users were associated with significantly lower risk of heart failure compared with those on GLP-1RA [hazard ratio = 0.183, 95 %CI = (0.045, 0.745)]. 1-year change in clinical parameters also favored use of SGLT2i over GLP-1RA, where the former was associated with a larger reduction in fasting glucose level [difference-in-difference = −0.87 mmol/L, 95 %CI = (−1.42, −0.33), p = 0.002]. The two groups had comparable direct medical costs after 1-year of follow-up. ConclusionPatients initiating SGLT2i experienced a significantly lower risk of heart failure than those on GLP-1RA, alongside better glycemic control through a larger reduction in fasting glucose level over one-year follow-up, while direct medical cost incurred was comparable to that of GLP-1RA.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

BackgroundType 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.MethodsPatients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.ResultsTreatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups.ConclusionsIn patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects.Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

Abstract P101: Primary Aldosteronism Screening In At-risk Populations

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA is associated with higher rates of cardiovascular, metabolic, and renal comorbidities as compared to equivalent primary hypertension (HTN). Objective: To evaluate the rates and patterns of PA screening across various at-risk populations. Methods: We performed a retrospective review of adult patients seen in a university-based outpatient setting between 1/1/17-6/30/20, who had HTN plus at least one of the following criteria: 1) taking ≥3 antihypertensive agents (resistant HTN); 2) age &lt;35; 3) obstructive sleep apnea (OSA); 4) hypokalemia; or 5) an adrenal mass. We excluded patients with adrenal insufficiency, congenital adrenal hyperplasia, severe renal disease, and end stage heart failure. Results: We identified 93,362 patients (54.6% men, mean age 64±16 y, 82.3% white, 12.8% black, 2.3% Asian) meeting at least one PA screening criterion. Of these, 3.4% were screened for PA. Screening occurred in 2.7% (1,813/66,185) of patients with resistant HTN; 4.2% of those with HTN and OSA (1,297/29,322) or hypokalemia (599/5,387); 5.1% of those &lt;35 y (461/8,573); and 46.5% (452/972) of patients with HTN and an adrenal mass. Multiple logistic regression showed that the odds of screening were highest in patients with hypokalemia: OR: 3.4 (3.2-3.7), and were independent of having atrial fibrillation or myocardial infarction. Among patients with resistant HTN and those with HTN and OSA, women vs. men (OR: 1.2-1.4) and blacks vs. all other races (OR: 2-2.6, p &lt;0.0001 for all) were more likely to be screened. Conversely, among patients &lt;35 y and those with adrenal masses, there were no race or sex differences. Although ~8 years younger, patients with resistant HTN and HTN+OSA screened had higher prevalence of chronic kidney disease, cerebrovascular accidents, dyslipidemia, and diabetes than those not screened. Conclusions: PA remains vastly under-recognized, even in large academic settings. Consideration for PA is given more often after comorbidities have developed. Enhancing awareness and screening rates for PA are critical for preventing cardio-renal and metabolic complications in many patients with HTN.

Abstract 62: Dietary Fibre Attenuates Hypertension By Reducing Macrophage Infiltration Via Gut Microbiota-Derived Metabolite-Sensing Receptors

High dietary fibre is fermented by the gut microbiota, resulting in the release of metabolites called short-chain fatty acids (SCFAs). Both fibre and SCFAs can reduce high blood pressure (BP) and its associated cardio-renal complications. However, the underlying mechanisms remain unclear. SCFAs can be detected by metabolite-sensing receptors GPR41 and GPR43, highly expressed by immune cells such as macrophages. We hypothesised that dietary fibre attenuates hypertension by modulating renal macrophage infiltration via metabolite-sensing receptors GPR41 and GPR43. To test this, we developed a novel GPR41/GPR43 double knockout (DKO) mice and characterised the cardiovascular and immune phenotype in both sham and angiotensin-II (Ang-II, 0.5mg/kg/day) treated DKO and wild-type (WT) mice (n=7-12 per group). WT Ang-II mice fed a high-fibre diet had significantly lower renal galectin-3 (p=0.0004), a macrophage marker, compared to WT Ang-II mice fed a low-fibre diet. Sham DKO mice on standard chow diet had no difference in BP or heart function but had higher kidney/tibia length index (p=0.049) and renal fibrosis levels compared to WT mice (p=0.004). Moreover, untreated DKO mice had higher numbers of renal macrophages compared to WT mice (p=0.002). Ang-II infusion of DKO mice resulted in higher BP (p&lt;0.0001), renal fibrosis (p=0.007), and mortality (hazard ratio=5.6) compared to WT mice. In the gut, we found significant inflammatory changes, gut barrier integrity disruption, gut microbiota and metabolome changes (all p&lt;0.05). We also found evidence of lipopolysaccharides (LPS) translocation from the gut into the circulation of DKO mice. In conclusion, we show that a high-fibre diet attenuates hypertension by modulating renal macrophages via the gut microbiota-derived metabolite-sensing GPR41 and GPR43 receptors. These receptors can be targeted as a novel treatment for hypertension.

Role of Selective Sodium-Glucose Co-Transporter-2 Inhibitors in Managing Cardio-Renal Complications in Type 2 Diabetes Mellitus: Beyond Glycemic Control.

Chronic kidney disease (CKD) and cardiovascular complications are the leading causes of death in type 2 diabetes mellitus. Apart from the standard therapy, which includes angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), lipid-lowering medication, and anti-platelet therapy, the new group of drugs termed the 'sodium-glucose co-transporter-2 (SGLT2) inhibitors' have shown promising results in managing complications arising from the cardiovascular and renal systems in diabetics. This article attempts to highlight the role and mechanism of action of this class of drugs. We reviewed 127 articles and analyses of randomized controlled trials using several drugs in the SGLT2 inhibitor family (sotagliflozin, canagliflozin, dapagliflozin, tofogliflozin) over the past five years, out of which 58 met the criteria and aim of the study. These articles were retrieved from PubMed, Google Scholar, and Medline data sources and assessed for quality using the assessment of multiple systematic reviews (AMSTAR) checklist and Cochrane risk-of-bias tool. Results from the review showed significant benefits in reducing progressive renal decline, blood pressure control, heart failure hospitalization, death from renal or cardiovascular complications, myocardial infarction, and stroke. This benefit is also seen in non-diabetic patients, hence postulating that these effects may not be solely due to glycemic control. There are several mechanisms with which it achieves this benefit with the most significant being its role on intraglomerular pressure. Other pathways include blood pressure control, natriuresis, ventricular remodeling, erythropoiesis, lipid metabolism, plasma volume, and electrolyte imbalance. It is clear that the role of SGLT2 inhibitors isn’t limited to glycemic control and they can achieve a wide array of functions by affecting different systems. More studies need to be done to completely understand this medication to improve the quality of life in diabetic and non-diabetic patients living with CKD and cardiovascular complications. The pharmacokinetics of this drug could also help set the basis for newer medications.

Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists.

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

1030-P: Cardiorenal Complications in Young-Onset T2DM Compared between White Caucasian and African American in the USA

Aim: Complex associations between T2DM, CKD and HF challenge treatment strategies and results in significant life years loss. Risk of CKD and HF in young- and usual-onset T2DM among White Caucasian (WC) and African American (AA) were explored.Methods: From nationally representative EMRs of USA, 1491672 WC and 31133 AA diagnosed with T2DM from 2000-2018 within age 18-39 /40-49/50-59/ 60-69 yrs were identified. The restricted mean time (RMT) to CKD and HF in AA and WC were compared, adjusting for anthropometric and time-varying disease confounders.Results: At T2DM Dx, 10 /12% and 2 /4% of WC /AA had existing CKD and HF; 48 /57% and 39 /32% had hypertension and dyslipidaemia. With mean 5 yrs follow-up, 95% CIs of CKD+HF incidence rates/1000PY were: (23-24) /(37-38) /(53-54) /(82-83) in 18-39 /40-49 /50-59/ 60-69 yrs grps for WC and (30-31) /(47-49) /(66-68) /(93-95) for AA.Compared to WC, AA had significantly higher risk of CKD and HF across all age groups (HR CI range: 1.1-2.4). In AA/WC aged 18-39 yrs, RMT (CI) in yrs to CKD [8.3 (7.8-8.7) /8.9 (8.5-9.2)] and HF [9.4 (8.6-10.3) /11.4 (9.8-12.9)] was on average only 3.2 /3.2 yrs and 2.7 /3.3 longer compared to those aged 60-69 yrs at Dx (Fig).Conclusion: Developing cardio-renal complications within 10 yrs of young-onset T2DM and significant higher risk among AA compared to WC call for more intense prevention strategies in young-onset population, particularly in AA.View largeDownload slideView largeDownload slide DisclosureS. K. Paul: Advisory Panel; Self; Sanofi, Consultant; Self; Roche Pharma. O. Montvida: None.

Dietary inflammatory index and cardiorenal function in women with diabetes and prediabetes

Background and aimsPrevious studies had shed a new light on the importance of multiple inflammatory mechanisms in the pathogenesis of arterial stiffness. The dietary inflammatory index (DII®) is a new tool for estimating the overall inflammatory potential of the diet. The aim of this study is to assess the association of the inflammatory potential of diet with peripheral arterial stiffness and renal function in women with diabetes and prediabetes. Methods and resultsThis is an observational cross-sectional study. A total of 2644 females aged 45–75 years were included for the study. Dietary intake in the past 12 months was assessed by a validated China National Nutrition and Health Survey 2002 (CNHS2002) food-frequency questionnaire. Energy-adjusted DII (E-DII) scores were calculated from daily dietary information. In a multivariable linear regression analysis adjusted for potential confounders, E-DII was positively associated with brachial ankle pulse wave velocity (baPWV) in participants with diabetes (β = 12.820; 95% CI = 2.565, 23.076; P = 0.014) and prediabetes (β = 29.025; 95% CI = 1.110, 56.940; P = 0.042), but not in females with normal glucose homeostasis. In addition, per unit increase of E-DII was significantly associated with lower eGFR (β = -1.363; 95% CI = -2.335, −0.392; P = 0.006) in patients with diabetes. ConclusionWe identified a direct association between E-DII and arterial stiffness, decreasedeGFR in middle-aged and elderly women with diabetes or prediabetes. Future studies are needed to verify and clarify the role of E-DII as an intervention target for cardiorenal complications of chronic hyperglycemia.

Non-adherence to antidiabetic and cardiovascular drugs in type 2 diabetes mellitus and its association with renal and cardiovascular outcomes: A narrative review.

Cardiovascular and renal complications are a major burden for individuals with type 2 diabetes mellitus (T2DM). Besides lifestyle interventions, current guidelines recommend combination drug therapy to prevent or delay the incidence and progression of comorbidities. However, non-adherence to pharmacotherapy is common in chronic conditions such as T2DM and a barrier to successful disease management. Numerous studies have associated medication non-adherence with worse outcome as well as higher health care costs. This narrative review provides (i) an overview on adherence measures used within and outside research settings, (ii) an estimate on the prevalence of non-adherence to antidiabetic and cardiovascular drugs in T2DM, and (iii) specifically focuses on the association of non-adherence to these drugs with renal and cardiovascular outcomes.

POS-323 INSIDE CKD: PROJECTING THE FUTURE BURDEN OF CHRONIC KIDNEY DISEASE IN EUROPE USING MICROSIMULATION MODELLING

Chronic kidney disease (CKD) is a debilitating and costly condition, affecting about 10% of people globally. Progression of CKD is associated with increased incidence of cardiovascular events, adverse renal outcomes and mortality, as well as high costs from renal replacement therapy (RRT) in end-stage renal disease. The future trajectories of CKD prevalence, progression and outcomes and their related costs, are critical considerations for public health and policy planning. Inside CKD aims to project, for the 2020–2025 period, the public health burden of CKD in Europe using a patient-level microsimulation-based model. An initial analysis for the UK was then adapted to other European countries. A virtual population was constructed using the following data from publicly available sources: country demographics and prevalence rates of CKD, RRTs and comorbidities, along with incidence rates of related complications. In the microsimulation, CKD stages were defined according to Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommendations. Patients were categorized according to estimated glomerular filtration rate (eGFR) and albuminuria status using data from the Health Survey for England (HSE) extrapolated to the UK population. Model validation and calibration were conducted following established methods for health economic modelling. RRT projections were calibrated against historical trends from the UK Renal Registry. Preliminary results for the UK demonstrate that, irrespective of population growth, the prevalence of CKD is projected to increase by 1% (from 13% to 14%) by 2025. The size of the CKD population is projected to grow from 9.07M in 2020 to 9.63M by 2025. Changes to the profile of CKD are also projected, with an increase in the more advanced stages (3b–5) of ~7% relative to the total CKD population by 2025. Increases in CKD prevalence are projected for all age categories (18–34, 35–64 and 65+ years); however, the 35–64-year-old age category is projected to have the largest relative impact, with a 20% rise in overall cases. RRT is projected to increase by 10.9% in the general UK population. Inside CKD is a validated microsimulation model that predicts increases in CKD prevalence and associated adverse cardiorenal complications over a 5-year period. The predicted increases pose a public health concern in the UK and potentially across Europe. The largest increase in CKD is predicted to be within the 35–64-year-old ‘working’ population. This could have wider societal implications due to possible productivity losses. Policy interventions aimed at early identification of patients and slowing of disease progression could lower this projected burden. Estimates from the whole of Europe will provide information at country level.

Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.

Diastolic dysfunction and impaired cardiac output reserve in dysmetabolic nonhuman primate with proteinuria.

Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE). A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178 ± 18 vs. 61 ± 3 mg/dL) accompanied by proteinuria (ACR: 134 ± 34 vs. 1.5 ± 0.4 mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1 ± 0.06 vs. 1.5 ± 0.13), but with preserved ejection fraction (EF: 65 ± 2 vs. 71 ± 3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40 μg/kg/min, 7 min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40 μg/kg/min) in both diastole (E/A: -12 ± 3 vs. -38 ± 5%) and systole (EF: 25 ± 3 vs. 33 ± 5%) as well as ~42% reduced cardiac output reserve (COR: 63 ± 8 vs. 105 ± 18%, p < 0.02) in the MetS compared to CTRL NHPs. These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.

НЕКОТОРЫЕ ВОПРОСЫ ЭПИДЕМИОЛОГИИ, ПАТОГЕНЕЗА, ДИАГНОСТИКИ И ЛЕЧЕНИЯ МНОЖЕСТВЕННОЙ МИЕЛОМЫ

A literature review article provides a comprehensive overview of literature related to epidemiology, pathogenesis, diagnosis and treatment of multiple myeloma (MM). Literature data show that MM has unclear patterns of the disease distribution, and there are trends in rising incidence. Although the aetiology of MM is not fully understood, according to most researchers, risk factors (RFs) leading to a progressively high incidence of MM include advanced age, male gender, exposure to harmful environmental factors (ionising radiation, chemical agents), family predisposition, an increased prevalence of autoimmune diseases and obesity. MM is characterised by the absence of specific clinical manifestations and similarity with other conditions, which is one of the factors associated with delay in diagnosis of MM. Damage to internal organs, particularly the heart and kidneys, a frequent complication of MM, leads to mutual burdening and is also one of the factors of adverse outcomes early during the disease. The International Myeloma Working Group (IMWG) diagnostic criteria and additional investigation techniques allow high accuracy to diagnose MM and its complications. Despite the development and introduction of new drugs and treatments, the long-term survival rates in MM patient remains low. Therefore there is a need for further research in this direction. Keywords: Multiple myeloma, cardiorenal complications, diagnostics, free light chains of immunoglobulins, treatment.

Inhibition of neprilysin with sacubitril without RAS blockage aggravates renal disease in Dahl SS rats

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.