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Atorvastatin Reduces Proteinuria in Non-Diabetic Chronic Kidney Disease Patients Partly via Lowering Serum Levels of Advanced Glycation End Products (AGEs)  [PDF]
Tsukasa Nakamura,Eiichi Sato,Nobuharu Fujiwara,Yasuhiro Kawagoe,Masayoshi Takeuchi,Sayaka Maeda,Sho-ichi Yamagishi
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.5.13069
Abstract: There is accumulating evidence that advanced glycation end products (AGEs) play a role in the development and progression of chronic kidney disease (CKD). We have previously found that atorvastatin treatment significantly reduces serum levels of AGEs in type 2 diabetic patients and subjects with non-alcoholic steatohepatitis in a cholesterol loweringindependent manner. In this study, we examined whether atorvastatin could reduce proteinuria partly via reduction of serum levels of AGEs in non-diabetic CKD patients. Ten non-diabetic normotensive stage I or II CKD patients with dyslipidemia were enrolled. Patients were treated with atorvastatin (10 mg/day) for one year. All subjects underwent determination of blood chemistries, proteinuria and serum levels of AGEs at baseline and after one year. Atorvastatin treatment for one year significantly decreased circulating levels of total cholesterol, LDL cholesterol, triglycerides and AGEs, while it increased HDL cholesterol levels. Further, although atorvastatin treatment did not affect estimated glomerular filtration rate, it significantly reduced proteinuria. In univariate analyses, proteinuria levels were correlated with total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol (inversely) and AGEs. Multiple stepwise regression analysis revealed that AGE level was a sole independent correlate of proteinuria. In this initial examination of the patients in this study, our present study suggests that atorvastatin could decrease proteinuria in non-diabetic CKD patients with dyslipidemia partly via reduction of serum levels of AGEs. Atorvastatin may have AGE-lowering effects in CKD patients as well that could contribute to renoprotective properties of this agent.
Atorvastatin Reduces Proteinuria in Non-Diabetic Chronic Kidney Disease Patients Partly via Lowering Serum Levels of Advanced Glycation End Products (AGEs)  [PDF]
Tsukasa Nakamura,Eiichi Sato,Nobuharu Fujiwara,Yasuhiro Kawagoe,Masayoshi Takeuchi,Sayaka Maeda,Sho-ichi Yamagishi
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.5.13069
Abstract: There is accumulating evidence that advanced glycation end products (AGEs) play a role in the development and progression of chronic kidney disease (CKD). We have previously found that atorvastatin treatment significantly reduces serum levels of AGEs in type 2 diabetic patients and subjects with non-alcoholic steatohepatitis in a cholesterol loweringindependent manner. In this study, we examined whether atorvastatin could reduce proteinuria partly via reduction of serum levels of AGEs in non-diabetic CKD patients. Ten non-diabetic normotensive stage I or II CKD patients with dyslipidemia were enrolled. Patients were treated with atorvastatin (10 mg/day) for one year. All subjects underwent determination of blood chemistries, proteinuria and serum levels of AGEs at baseline and after one year. Atorvastatin treatment for one year significantly decreased circulating levels of total cholesterol, LDL cholesterol, triglycerides and AGEs, while it increased HDL cholesterol levels. Further, although atorvastatin treatment did not affect estimated glomerular filtration rate, it significantly reduced proteinuria. In univariate analyses, proteinuria levels were correlated with total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol (inversely) and AGEs. Multiple stepwise regression analysis revealed that AGE level was a sole independent correlate of proteinuria. In this initial examination of the patients in this study, our present study suggests that atorvastatin could decrease proteinuria in non-diabetic CKD patients with dyslipidemia partly via reduction of serum levels of AGEs. Atorvastatin may have AGE-lowering effects in CKD patients as well that could contribute to renoprotective properties of this agent.
Age and kidney function are the primary correlates of fasting plasma total homocysteine levels in non-diabetic and diabetic adults. Results from the 1999–2002 National Health and Nutrition Examination Survey
Glen E Duncan, Sierra M Li, Xiao-Hua Zhou
Nutrition & Metabolism , 2005, DOI: 10.1186/1743-7075-2-13
Abstract: Analysis of data on adults (≥ 20y) who had fasted at least 8 hours, from the National Health and Nutrition Examination Survey (1999–2000 and 2001–2002). Subjects with no self-report history of diabetes were grouped according to fasting plasma glucose status as normal (< 100 mg/dL = NFG, n = 2,244), impaired (≥ 100 < 126 mg/dL = IFG, n = 1,108), or a provisional diagnosis of diabetes (≥ 126 mg/dL = DFG, n = 133). Subjects with a self-report history of diabetes (n = 275) were examined separately.Fasting tHcy was higher (Ps < 0.01) among non-diabetic subjects with DFG and IFG, compared to NFG (median [95% confidence interval] = 8.6 [8.0–9.2], 8.3 [8.1–8.5], and 7.4 [7.3–7.5] μmol/L, respectively). Diabetic subjects had levels similar to non-diabetic subjects with DFG and IFG (8.3 [7.9–8.6] μmol/L). Age and estimated creatinine clearance were strong correlates of fasting tHcy among non-diabetic subjects (r = 0.38 to 0.44 and r = -0.35 to -0.46, respectively) and diabetic subjects (r = 0.41 and r = -0.46, respectively) (Ps < 0.001), while fasting glucose and glycohemoglobin (HbA1c) were weaker (but still significant) correlates of tHcy in non-diabetic and diabetic subjects. Fasting glucose status was not a significant independent predictor of fasting tHcy levels in non-diabetic subjects, and HbA1c was not a significant independent predictor of tHcy in diabetic subjects (Ps > 0.05).Fasting tHcy levels are elevated among non-diabetic adults with elevated fasting glucose levels, compared to persons with normal fasting glucose levels, and among diabetic adults. However, elevations in fasting tHcy appear to be mediated primarily by age and kidney function, and not by measures of glucose metabolism.Clinical studies have established that individuals with diabetes have a two- to six-fold increased risk for various manifestations of cardiovascular disease (CVD), compared to age matched nondiabetic subjects [1-3]. Although individuals with diabetes have a higher prevalence of trad
Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults
Ho Sik Shin, Yeon Soon Jung, Hark Rim
BMC Nephrology , 2011, DOI: 10.1186/1471-2369-12-29
Abstract: We retrospectively reviewed the medical records of Korean adults who were evaluated at Kosin University Gospel Hospital (Busan, Republic of Korea) during a five-year period from January 2005 to December 2009. We evaluated the relationships among serum bilirubin concentration, estimated glomerular filtration rate (eGFR) and 24-hour urinary protein excretion in a sample of 1363 Korean adults aged 18 years or older.The values of eGFR <60 mL/min/1.73 m2 and 24-hour urine albumin ≥150 mg/day were observed in 26.1% (n = 356) and 40.5% (n = 553) of subjects, respectively. Fasting glucose levels ≥126 mg/dL were observed in 44.9% (n = 612) of the total sample. After adjustment for potential confounding factors including demographic characteristics, comorbidities and other laboratory measures, total serum bilirubin was positively associated with eGFR and negatively associated with proteinuria both in the whole cohort and in a subgroup of diabetic individuals.To our knowledge, this is the first hospital-based study specifically aimed at examining the relationships among serum total bilirubin concentration, 24-hour urine protein and kidney function in Korean adults. We demonstrated that serum total bilirubin concentration was negatively correlated with 24-hour urine protein and positively correlated with eGFR in Korean non-diabetic and diabetic adults.The prevalence of chronic kidney disease is increasing worldwide [1,2]. Reduced eGFR and abnormal proteinuria have been associated with increased risk of end stage renal disease (ESRD), cardiovascular disease and other comorbidities [3-6]. Because renal disease often progresses to ESRD, the identification of risk factors for kidney disease progression is essential.Increased concentrations of serum bilirubin have long been used as a marker of liver dysfunction. In addition, serum bilirubin is not merely an end product of heme degradation but is also a potent antioxidant that acts via inhibitions of NADPH oxidase, a key source of ox
Divergences in antihypertensive therapy in special situations in nephrology
Lemos, Marcelo Montebello;Pedrosa, Alessandra Coelho;Tavares, Alze Pereira;Góes, Miguel ?ngelo;Draibe, Sérgio Ant?nio;Sesso, Ricardo;
Sao Paulo Medical Journal , 2008, DOI: 10.1590/S1516-31802008000100007
Abstract: context and objective: the choice of an antihypertensive drug is based on several criteria and specific situations give rise to doubt and controversy. the aim here was to evaluate physicians? approaches towards treatment with antihypertensive agents in specific situations. design and setting: cross-sectional study, at universidade federal de s?o paulo, s?o paulo. methods: a questionnaire was applied during a nephrology meeting to evaluate individual approaches towards each hypothetical clinical situation. the questionnaire consisted of five multiple-choice questions (clinical cases) concerning controversial aspects of antihypertensive therapy. results: a total of 165 questionnaires were analyzed. most participants were nephrologists (93.2%). there was a preference for angiotensin-converting enzyme (ace) inhibitors in at least two of the cases. only 57.2% of the physicians were correct in choosing beta-blockers as the first-line drugs for patients with ischemic coronary disease. moreover, 66.2% chose ace inhibitors as the first-line drugs for patients with chronic kidney disease and proteinuria. about 5% of the physicians did not follow the current recommendations for the use of ace inhibitors in diabetic patients with microalbuminuria. the most controversial question concerned the first-line drug for advanced chronic kidney disease. most physicians were correct in choosing calcium channel blockers and avoiding ace inhibitors in renovascular hypertension in the case of a patient with a single functioning kidney. conclusions: most physicians adopted the correct approach, but some had an alternative strategy for the same situations that was not based on evidence.
Diabetic Glomerulopathy: Pathogenesis and Management  [cached]
Schmidt Susanne,Ismail Abdullah,Ritz Eberhard
Saudi Journal of Kidney Diseases and Transplantation , 2000,
Abstract: Although not all renal disease that diabetic patients develop is due to diabetic glomerulosclerosis, the great majority of patients progressing to advanced renal failure suffer from diffuse or nodular (Kimmelstiel Wilson′s) diabetic glomerulosclerosis. This condition has become the single most frequent cause of end-stage renal failure in the Western world. Recent studies indicate that an interplay between genetic predisposition and other factors such as hyperglycemia, blood pressure, age, gender, smoking and ethnicity, predispose to nephropathy both in type 1 and type 2 diabetes mellitus. It has also become clear that trace albuminuria ("microalbuminuria") provides a unique opportunity to recognize incipient renal involvement early on, particularly in type 1 and less specifically in type 2 diabetes. Increasing evidence indicates that early intervention delays progression of nephropathy. Factors which promote progression of nephropathy include hypertension, proteinuria, smoking, poor glycemic control and, less certainly, high dietary protein intake and hyperlipidemia. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with end-stage renal failure include (i) prevention of diabetes (mainly type 2), (ii) glycemic control to prevent onset of renal involvement and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy. Survival of diabetic patients on dialysis and after transplantation is inferior to that of non-diabetic patients, mainly because of high rate of cardiovascular death. There is consensus that in the absence of major vascular disease the best treatment is renal transplantation in the type 2 diabetic patient and combined kidney and pancreas transplantation in the type 1 diabetic patient.
Cálculo del impacto económico para Chile del uso de losartán en diabéticos tipo 2 con nefropatía diabética, basado en resultados del estudio RENAAL Economic impact of Losartan use in type 2 diabetic patients with nephropathy  [cached]
Fernando González F,Verónica Fuentes C,Catalina Castro H,Juan Pablo Santelices L
Revista médica de Chile , 2009,
Abstract: Background: The study RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) demonstrated that Losartan was more effective lo reduce the progression of kidney disease in diabetic patients with proteinuria and a reduction in glomerular filtration rate. Aim: To perform a cost benefit analysis of Losartan use from provider and payer points of view. Material and methods: Published data of the RENAAL study was analyzed. The costs of the use or not use of Losartan in patients with diabetic nephropathy were compared in terms of total costs of the disease including medications, hospital admissions for myocardial infarction, cerebrovascular accidents and congestive cardiac failure and the costs of chronic hemodialysis. Results: The reduction in antihypertensive medication use, hospital admissions, and the delay in dialysis requirement from a mean of 65 to 79 months induced by Losartan use, results in net savings of $7,576,135 per patient, at 3.5 years of intervention. The figure does not change using different sensitivity scenarios. Conclusions: The eventual use of Losartan in type 2 diabetic patients results in important savings.
Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease  [PDF]
Sumant S. Chugh,Camille Macé,Lionel C. Clement,Maria Del Nogal Avila,Caroline B. Marshall
Frontiers in Pharmacology , 2014, DOI: 10.3389/fphar.2014.00023
Abstract: Current drugs used to treat proteinuric disorders of the kidney have been borrowed from other branches of medicine, and are only partially effective. The discovery of a central, mechanistic role played by two different forms of the secreted glycoprotein angiopoietin-like 4 (Angptl4) in human and experimental glomerular disease has opened new treatment avenues. Localized upregulation of a hyposialylated form (lacks sialic acid residues) of Angptl4 secreted by podocytes induces the cardinal morphological and clinical manifestations of human minimal change disease, and is also being increasingly recognized as a significant contributor toward proteinuria in experimental diabetic nephropathy. Oral treatment with low doses of N-acetyl-D-mannosamine, a naturally occurring precursor of sialic acid, improves sialylation of Angptl4 in vivo, and reduces proteinuria by over 40%. By contrast, a sialylated circulating form of Angptl4, mostly secreted from skeletal muscle, heart and adipose tissue in all major primary glomerular diseases, reduces proteinuria while also causing hypertriglyceridemia. Intravenous administration of recombinant human Angptl4 mutated to avoid hypertriglyceridemia and cleavage has remarkable efficacy in reducing proteinuria by as much as 65% for 2 weeks after a single low dose. Both interventions are mechanistically relevant, utilize naturally occurring pathways, and represent new generation therapeutic agents for chronic kidney disease related to glomerular disorders.
MicroRNAs in Diabetic Kidney Disease  [PDF]
Rong Li,Arthur C. K. Chung,Xueqing Yu,Hui Y. Lan
International Journal of Endocrinology , 2014, DOI: 10.1155/2014/593956
Abstract: Rapid growth of diabetes and diabetic kidney disease exerts a great burden on society. Owing to the lack of effective treatments for diabetic kidney disease, treatment relies on drugs that either reduces its progression or involve renal replacement therapies, such as dialysis and kidney transplantation. It is urgent to search for biomarkers for early diagnosis and effective therapy. The discovery of microRNAs had lead to a new era of post-transcriptional regulators of gene expression. Studies from cells, experimental animal models and patients under diabetic conditions demonstrate that expression patterns of microRNAs are altered during the progression of diabetic kidney disease. Functional studies indicate that the ability of microRNAs to bind 3′ untranslated region of messenger RNA not only shows their capability to regulate expression of target genes, but also their therapeutic potential to diabetic kidney disease. The presence of microRNAs in plasma, serum, and urine has been shown to be possible biomarkers in diabetic kidney disease. Therefore, identification of the pathogenic role of microRNAs possesses an important clinical impact in terms of prevention and treatment of progression in diabetic kidney disease because it allows us to design novel and specific therapies and diagnostic tools for diabetic kidney disease. 1. Epidemiology and Diabetes The prevalence of diabetes is rising worldwide and is expected to reach the devastating number of 439 million by the year 2030 from 285 million in 2010 [1]. This huge elevation is attributed to an escalating tendency towards sedentary lifestyle and westernized choice of diet, leading to obesity. Furthermore, the age of onset for the type 2 diabetic patients is showing a trend to begin in youths [2]. Diabetes is a significant public health concern as its rising incidence has greatly increased the cost of treating both diabetes and its numerous debilitating complications. 2. Diabetic Kidney Disease Diabetic kidney disease is one of the diabetic microvascular complications. Type 1 and type 2 diabetes are distinct in etiology and pathogenesis. In spite of different morphological changes of renal injury in type 1 and type 2 diabetic patients [3], type 1 and type 2 diabetic patients have similar risks of renal injury in diseased kidney [4]. The characteristics of diabetic renal injury includes the effacement of podocyte foot processes, gradual mesangial cell (MC) proliferation and hypertrophy, excessive accumulation of extracellular matrix (ECM) proteins, mesangial expansion, and thickening of the glomerular
Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study
Prasad Bichu, Ravi Nistala, Asma Khan, James R Sowers, Adam Whaley-Connell
Vascular Health and Risk Management , 2009, DOI: http://dx.doi.org/10.2147/VHRM.S3121
Abstract: ngiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study Review (9547) Total Article Views Authors: Prasad Bichu, Ravi Nistala, Asma Khan, James R Sowers, Adam Whaley-Connell Published Date December 2008 Volume 2009:5 Pages 129 - 140 DOI: http://dx.doi.org/10.2147/VHRM.S3121 Prasad Bichu1, Ravi Nistala1, Asma Khan2, James R Sowers2, Adam Whaley-Connell1 1Divisions of Nephrology and Endocrinology; 2Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia Missouri, USA Abstract: Diabetic kidney disease is characterized by persistent albuminuria (>300 mg/dl or >200 μg/min) that is confirmed on at least 2 occasions 3 to 6 months apart, with a progressive decline in the glomerular filtration rate (GFR), elevated arterial blood pressure, and an increased risk for cardiovascular morbidity and mortality. Diabetic kidney disease is the leading cause of end stage renal disease (ESRD) prompting investigators to evaluate mechanisms by which to slow disease progression. One such mechanism is to block the activity of angiotensin II at the receptor site and agents that follow this mechanism are referred to as angiotensin receptor blockers (ARB). There is sufficient clinical evidence to support that ARB have protective effects on kidney function in patients with diabetes and hypertension. However, in the past decade there have been few investigations comparing individual ARBs on renal outcomes. Telmisartan, a lipophilic ARB with a long half-life, has been hypothesized to have a greater anti-proteinuric effect when compared to the shorter acting losartan. Therefore, the A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO) trial sought to investigate renal and cardiovascular endpoints. In this review, we discuss the pathophysiology of diabetic kidney disease and implications of the AMADEO trial in the context of current understanding from recent outcome trials.
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