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Renoprotection and surrogate

Motoaki Sano, Makoto Takei, Yasuyuki Shiraishi, Yoshihiko Suzuki
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration...
December 2016: Journal of Clinical Medicine Research
Usha Panchapakesan, Carol Pollock
Despite major advances in the understanding of the molecular mechanisms that underpin the development of diabetic kidney disease, current best practice still leaves a significant proportion of patients with end-stage kidney disease requiring renal replacement therapy. This is on a background of an increasing diabetes epidemic worldwide. Although kidney failure is a major cause of morbidity the main cause of death remains cardiovascular in nature. Hence, diabetic therapies which are both "cardio-renal" protective seem the logical way forward...
2015: Frontiers in Immunology
Hiddo J Lambers Heerspink, Tobias F Kröpelin, Jarno Hoekman, Dick de Zeeuw
Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on albuminuria and ESRD to more reliably delineate the association between changes in albuminuria and ESRD...
August 2015: Journal of the American Society of Nephrology: JASN
Sara S Roscioni, Hiddo J Lambers Heerspink, Dick de Zeeuw
Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out...
July 2014: Kidney International
Frederik Persson, Peter Rossing
Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations...
March 2014: Advances in Chronic Kidney Disease
Hamid Nasri
Currently many patients with chronic renal failure have profited from the use of erythropoietin to correct anemia (1,2). In chronic kidney disease, anemia is believed to be a surrogate index for tissue hypoxia that continues preexisting renal tissue injury (1-3). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and facilitates erythropoiesis. It is a 30.4 kD glycoprotein and class I cytokine containing 165 amino acids (3,4). Approximately 90% of systemic erythropoietin in adults is produced by peritubular interstitial fibroblasts in the renal cortex and outer medulla of the kidney (3-5)...
2014: Cell Journal
Joseph Fomusi Ndisang, Ashok Jadhav
Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type 1 diabetes is not completely elucidated. Administering the HO inducer, hemin, to streptozotocin-diabetic rats suppressed renal proinflammatory macrophage-M1 phenotype alongside several proinflammatory agents, chemokines, and cytokines including macrophage inflammatory protein 1α (MIP-1α), macrophage-chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, IL-6, nuclear factor-κB (NF-κB), and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB...
January 2014: Endocrinology
Samir G Mallat
Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition...
2013: Cardiovascular Diabetology
László Bajnok
From the evaluated ONTARGET, ALTITUDE, ACCOMPLISH, ROADMAP, and ACCORD-BP studies a conclusion can be drawn that though microalbuminuria/proteinuria is a strong epidemiological biomarker, in interventional studies it is not necessarily a reliable surrogate endpoint as actual renal function may change in an opposite way. Namely, some therapeutic measures improving microalbuminuria/proteinuria may actually worsen renal function. In case of procedures such as blood pressure lowering or measure of RAS blockade an optimum point on a J-curve may exist...
February 17, 2013: Orvosi Hetilap
Helmut Schiffl, Susanne M Lang, Rainald Fischer
PURPOSE: Residual renal function (RRF) contributes to dialysis adequacy, quality of life and survival of hemodialysis patients. There is an ongoing debate whether better preservation of residual renal function is the result of chronic fluid volume overload. Our prospective investigation analyzed the effects of different dialytic therapies on RRF and left ventricular hypertrophy, which may be considered--at least in part--a surrogate marker of chronic fluid overload. METHODS: Two cohorts of end-stage renal disease patients initiating renal replacement therapy (high efficiency post-dilution on-line hemodiafiltration (HDF) in 58 patients, conventional hemodialysis (HD) in 60 patients) were prospectively followed up...
October 2013: International Urology and Nephrology
Usha Panchapakesan, Amanda Mather, Carol Pollock
Although there have been major advances in the understanding of the molecular mechanisms that contribute to the development of diabetic nephropathy, current best practice still leaves a significant treatment gap. The incidence of diabetes and associated nephropathy is increasing, with the main cause of mortality being related to cardiovascular causes. Novel therapies which are both 'cardio-renal'-protective seem the logical way forward. In the present review, we discuss the GLP-1 (glucagon-like peptide-1) receptor agonists and DPP-4 (dipeptidyl peptidase-4) inhibitors (incretin-based therapies), which are novel antidiabetic agents used in clinical practice and their role in diabetic nephropathy with specific focus on renoprotection and surrogate markers of cardiovascular disease...
January 2013: Clinical Science (1979-)
Alejandro R Chade, Silvia Kelsen
Renal microvascular (MV) damage and loss contribute to the progression of renal injury in renovascular disease (RVD). Whether a targeted intervention in renal microcirculation could reverse renal damage is unknown. We hypothesized that intrarenal vascular endothelial growth factor (VEGF) therapy will reverse renal dysfunction and decrease renal injury in experimental RVD. Unilateral renal artery stenosis (RAS) was induced in 14 pigs, as a surrogate of chronic RVD. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo in the stenotic kidney using multidetector computed tomography (CT)...
May 15, 2012: American Journal of Physiology. Renal Physiology
Neeraj Dhaun, Iain M MacIntyre, Debbie Kerr, Vanessa Melville, Neil R Johnston, Scott Haughie, Jane Goddard, David J Webb
Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk...
April 2011: Hypertension
Esther Meijer, Stephan J L Bakker, Eric J van der Jagt, Gerjan Navis, Paul E de Jong, Joachim Struck, Ron T Gansevoort
BACKGROUND AND OBJECTIVES: Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay...
February 2011: Clinical Journal of the American Society of Nephrology: CJASN
Jinn-Yuh Guh
Chronic kidney disease (CKD) is defined according to a decrease in the glomerular filtration rate and kidney damage such as proteinuria or albuminuria. Dip-stick proteinuria is only sensitive to albumin and correlates poorly with quantitative 24 h proteinuria, the most commonly used measure in renoprotective randomized controlled clinical trials (RCT). The amount of proteinuria correlates with the efficacy of angiotensin-converting enzyme inhibitors in non-diabetics in RCT. Random urine protein to creatinine ratio (PCR) or albumin to creatinine ratio (ACR) correlates with 24 h urinary excretion...
June 2010: Nephrology
Naoto Tominaga, Annie Robert, Yuko Izuhara, Shuichi Ohtomo, Takashi Dan, Kazuo Chihara, Kiyoshi Kurokawa, Charles Van Ypersele de Strihou, Toshio Miyata
AIM: Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria. METHODS: Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4-160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed...
September 2009: Nephrology
Macaulay A Onuigbo
Despite reported renoprotection with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and notwithstanding their increased use, we continue to experience an epidemic of acute renal failure (ARF)/chronic kidney disease/end-stage renal disease. Consequently, concerns about iatrogenic renal failure have resurfaced. Different analysis of these trials revealed flaws such as recruitment of relatively younger patients with preserved baseline renal function, common utilization of lower end doses of ACEIs/ARBs, high drug discontinuation rates, excessive use of surrogate endpoints, inadequate reporting of adverse effects, and short duration studies...
2009: Nephron. Clinical Practice
Raymond O Estacio
Cardiovascular (CV) and renal complications associated with diabetes can be attenuated with antihypertensives that work on the renin-angiotensin-aldosterone system (RAAS),particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly direct renin inhibitors (DRIs). Cardioprotective and renoprotective benefits are independent of the blood pressure-lowering effect of the RAAS inhibitor. Given more complete RAAS blockade, evidence has suggested that the use of ACE inhibitor/ARB combination therapy may provide greater target organ protection...
May 2009: Postgraduate Medicine
Cynthia A Sanoski
Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity...
February 2009: Pharmacotherapy
Shiming Zhu, Yuying Liu, Liqi Wang, Qing H Meng
BACKGROUND: Evidence suggests that transforming growth factor-beta1 (TGF-beta(1)) is associated with target organ damage in hypertension. This study aimed to investigate the relationship between TGF-beta(1) levels and kidney damage and renoprotective effects of angiotensin-converting enzyme inhibitor and/or angiotensin II type 1 receptor blocker in patients with essential hypertension (EH). METHODS: A total of 156 patients with EH were enrolled and grouped according to albumin-to-creatinine ratio (ACR)...
September 2008: Nephrology, Dialysis, Transplantation
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