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1.
How Low Do We Go (in the Post-SPRINT Era)?
Burgner, A, Lewis, JB
Advances in chronic kidney disease. 2019;(2):110-116
Abstract
Hypertension is frequently both a cause and complication of CKD. The optimal blood pressure target in CKD has been of hot debate over the decades with little data to inform the goals. Here, we review the data from the Systolic Blood Pressure Intervention Trial (SPRINT), Modification of Diet in Renal Disease (MDRD), African American Study of Kidney Disease and Hypertension (AASK), Ramipril Efficacy in Nephropathy-2 (REIN-2), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials to use the available evidence to better inform what blood pressure goal should be recommended in patients with CKD and to answer the question "How low should we go?".
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2.
Nonproteinuric progressive diabetic kidney disease.
Zoccali, C, Mallamaci, F
Current opinion in nephrology and hypertension. 2019;(3):227-232
Abstract
PURPOSE OF REVIEW We will summarize recent epidemiological observations on the risk for overt diabetic kidney disease (DKD) in nonproteinuric patients, will focus on novel studies based on a proteomic biomarker of DKD and will discuss the possibility of preventing the progression of DKD in nonproteinuric patients by sodium glucose transporter 2 (SGLT2) inhibitors. RECENT FINDINGS Although less frequently than in type 2 diabetes, DKD may develop also in nonproteinuric type 1 diabetes. However, the progression rate to kidney failure in nonproteinuric diabetic people is much lower than in proteinuric ones. A new proteomic biomarker, the chronic kidney disease (CKD)273, reliably predicts the risk of incident micro and macroalbuminuria and of CKD in nonalbuminuric diabetic people. SGLT2 inhibition markedly reduces albuminuria in macro and microalbuminuric patients and discernibly mitigates albumin excretion also in those with albuminuria in the normal range. SUMMARY Studies focusing on risk factors for DKD in nonproteinuric patients are a clinical research priority. The CKD273 classifier is a promising biomarker for the early identification of nonproteinuric patients at high risk for progressive DKD. Empagliflozin and SGLT2 inhibitors may have a favorable impact on the progression of DKD in nonalbuminuric diabetic people, a hypothesis to be tested in specific clinical trials.
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3.
Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity.
Komici, K, Femminella, GD, de Lucia, C, Cannavo, A, Bencivenga, L, Corbi, G, Leosco, D, Ferrara, N, Rengo, G
Aging clinical and experimental research. 2019;(3):321-330
Abstract
Diabetes mellitus (DM) and heart failure (HF) are frequent comorbidities among elderly patients. HF, a leading cause of mortality and morbidity worldwide, is characterized by sympathetic nervous system hyperactivity. The prevalence of diabetes mellitus (DM) is rapidly growing and the risk of developing HF is higher among DM patients. DM is responsible for several macro- and micro-angiopathies that contribute to the development of coronary artery disease (CAD), peripheral artery disease, retinopathy, neuropathy and diabetic nephropathy (DN) as well. Independently of CAD, chronic kidney disease (CKD) and DM increase the risk of HF. Individuals with diabetic nephropathy are likely to present a distinct pathological condition, defined as diabetic cardiomyopathy, even in the absence of hypertension or CAD, whose pathogenesis is only partially known. However, several hypotheses have been proposed to explain the mechanism of diabetic cardiomyopathy: increased oxidative stress, altered substrate metabolism, mitochondrial dysfunction, activation of renin-angiotensin-aldosterone system (RAAS), insulin resistance, and autonomic dysfunction. In this review, we will focus on the involvement of sympathetic system hyperactivity in the diabetic nephropathy.
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4.
SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects.
Garofalo, C, Borrelli, S, Liberti, ME, Andreucci, M, Conte, G, Minutolo, R, Provenzano, M, De Nicola, L
Medicina (Kaunas, Lithuania). 2019;(6)
Abstract
The burden of diabetic kidney disease (DKD) has increased worldwide in the last two decades. Besides the growth of diabetic population, the main contributors to this phenomenon are the absence of novel nephroprotective drugs and the limited efficacy of those currently available, that is, the inhibitors of renin-angiotensin system. Nephroprotection in DKD therefore remains a major unmet need. Three recent trials testing effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have produced great expectations on this therapy by consistently evidencing positive effects on hyperglycemia control, and more importantly, on the cardiovascular outcome of type 2 diabetes mellitus. Notably, these trials also disclosed nephroprotective effects when renal outcomes (glomerular filtration rate and albuminuria) were analyzed as secondary endpoints. On the other hand, the use of SGLT2-i can be potentially associated with some adverse effects. However, the balance between positive and negative effects is in favor of the former. The recent results of Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation Study and of other trials specifically testing these drugs in the population with chronic kidney disease, either diabetic or non-diabetic, do contribute to further improving our knowledge of these antihyperglycemic drugs. Here, we review the current state of the art of SGLT2-i by addressing all aspects of therapy, from the pathophysiological basis to clinical effectiveness.
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5.
SGLT2 inhibitors in patients with type 2 diabetes and renal disease: overview of current evidence.
Davidson, JA
Postgraduate medicine. 2019;(4):251-260
Abstract
Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is associated with poor clinical outcomes, including an increased risk of all-cause and cardiovascular mortality, as well as adverse economic and social effects. Slowing the development and progression of CKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering that include cardiovascular benefits and potential renoprotective effects. Although the glucose-lowering efficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m2. Clinical evidence has indicated that these agents can reduce the risk of development or worsening of albuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressure lowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory processes, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressure-lowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute to reduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies in these patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding to the growing evidence of the potential renoprotective effects of these agents in patients with T2DM. Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinical role of SGLT2 inhibitors in slowing the development and progression of renal impairment in individuals with T2DM.
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6.
Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity.
Efe, O, Verma, A, Waikar, SS
Current opinion in nephrology and hypertension. 2019;(4):316-320
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Free full text
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Abstract
PURPOSE OF REVIEW Hyperoxaluria can cause kidney disease through multiple mechanisms, including tubular obstruction from calcium oxalate crystals, sterile inflammation, and tubular epithelial cell injury. Hyperoxaluria is also observed in individuals with diabetes mellitus and obesity, which are in turn risk factors for chronic kidney disease (CKD). Whether hyperoxaluria is a potential mediator of increased risk of CKD in diabetes mellitus and obesity is unknown. RECENT FINDINGS Individuals with diabetes have increased levels of plasma glyoxal (a protein glycation product) and glyoxylate, both of which are precursors for oxalate. Increased gut absorption of oxalate in obesity may be because of obesity-associated inflammation. A recent study in individuals with CKD found that higher 24 h urinary oxalate excretion was independently associated with increased risk of kidney disease progression, especially in individuals with diabetes and obesity. SUMMARY Both diabetes mellitus and obesity are associated with higher urinary oxalate excretion through distinct mechanisms. Hyperoxaluria could be a mechanism by which kidney disease develops in individuals with diabetes mellitus or obesity and could also contribute to progressive loss of renal function. Future research on pharmacologic or dietary measures to limit oxalate absorption or generation are required to test whether lowering urinary oxalate excretion is beneficial in preventing kidney disease development and progression in diabetes mellitus and obesity.
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7.
Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection: JACC Review Topic of the Week.
Cherney, DZ, Odutayo, A, Aronson, R, Ezekowitz, J, Parker, JD
Journal of the American College of Cardiology. 2019;(20):2511-2524
Abstract
Poorly controlled type 2 diabetes mellitus is associated with the development of cardiovascular and renal complications, resulting in significant morbidity and mortality. Intensive glycemic control has been a major focus for clinical trials and novel drug development. However, narrow treatment strategies developed strictly for glycemic control did not confer a large risk reduction in cardiovascular events. There were also only modest effects in reducing the progression of diabetic kidney disease. Recent cardiovascular safety trials and the dedicated renal protection trial CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) have shown that the sodium-glucose cotransporter-2 (SGLT2) inhibitors, a newer generation of antihyperglycemic agents, improve both cardiovascular and renal outcomes when added to guideline-recommended treatment. This review examines the current evidence on the mechanism underlying the cardiorenal effects of SGLT2 inhibitors and summarizes clinical trial evidence and safety data related to the use of SGLT2 inhibitors for cardiovascular and renal protection.
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8.
Lipid mediators of insulin signaling in diabetic kidney disease.
Mitrofanova, A, Sosa, MA, Fornoni, A
American journal of physiology. Renal physiology. 2019;(5):F1241-F1252
Abstract
Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signaling. This review summarizes the novel knowledge that intracellular lipids such as cholesterol and sphingolipids are major determinants of podocyte insulin signaling. In particular, the implications of these lipids on DKD development, progression, and treatment will be addressed.
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9.
Demethoxycurcumin: A naturally occurring curcumin analogue for treating non-cancerous diseases.
Hatamipour, M, Ramezani, M, Tabassi, SAS, Johnston, TP, Sahebkar, A
Journal of cellular physiology. 2019;(11):19320-19330
Abstract
Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti-inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end-products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions.
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10.
Impact of CVOTs in primary and secondary prevention of kidney disease.
De Cosmo, S, Viazzi, F, Piscitelli, P, Leoncini, G, Mirijello, A, Bonino, B, Pontremoli, R
Diabetes research and clinical practice. 2019;:107907
Abstract
Type 2 diabetes mellitus is the leading cause of end stage renal disease worldwide. Diabetic kidney disease, whose main clinical manifestations are albuminuria and decline of glomerular filtration rate, affects up to 40% of patients. Sodium Glucose cotransporter-2 inhibitors (SGLT2-is) and Glucagon-like peptide-1 receptor agonists (GLP-1ras) are new classes of anti-hyperglycemic drugs which have demonstrated to improve renal outcome. Renal benefits of both SGLT2-is and GLP-1ras are acknowledged from data of large randomized phase III clinical trials conducted to assess their cardiovascular safety. In this review, we will focus on renal results of major cardiovascular outcome trials, and we will describe direct and indirect mechanisms through which they confer renal protection.