Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.

AIM To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients. METHODS Prospective randomized 2-way cross over study; T2DM patients with (micro)albuminuria and/or hypertension underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) at baseline, after one month of enalapril (20 mgqd), and after one month of candesartan (16 mgqd). Each BOLD-MRI was performed before and after the administration of furosemide. The mean R₂* (=1/T₂*) values in the medulla and cortex were calculated, a low R₂* indicating high tissue oxygenation. RESULTS Twelve patients (mean age: 60 ± 11 years, eGFR: 62 ± 22 ml/min/1.73 m(2)) completed the study. Neither chronic enalapril nor candesartan intake modified renal cortical or medullary R₂* levels. Furosemide significantly decreased cortical and medullary R₂* levels suggesting a transient increase in renal oxygenation. Medullary R₂* levels correlated positively with urinary sodium excretion and systemic blood pressure, suggesting lower renal oxygenation at higher dietary sodium intake and blood pressure; cortical R₂* levels correlated positively with glycemia and HbA1c. CONCLUSION RAS blockade does not seem to increase renal tissue oxygenation in T2DM hypertensive patients. The response to furosemide and the association with 24 h urinary sodium excretion emphasize the crucial role of renal sodium handling as one of the main determinants of renal tissue oxygenation.

[1]  Jeremiah Stamler,et al.  Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. , 1988 .

[2]  M. Khamaisi,et al.  Renal Parenchymal Hypoxia, Hypoxia Response and the Progression of Chronic Kidney Disease , 2008, American Journal of Nephrology.

[3]  Yutaka Imai,et al.  European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement , 2003, Journal of hypertension.

[4]  Pottumarthi V. Prasad,et al.  Evaluation of Intra-Renal Oxygenation by BOLD MRI , 2006, Nephron Clinical Practice.

[5]  M. Brezis,et al.  Hypoxia of the renal medulla--its implications for disease. , 1995, The New England journal of medicine.

[6]  Visualization and quantification of renal R2* changes during water diuresis , 2003, Journal of magnetic resonance imaging : JMRI.

[7]  L. Lerman,et al.  Increased hypoxia and reduced renal tubular response to furosemide detected by BOLD magnetic resonance imaging in swine renovascular hypertension. , 2009, American journal of physiology. Renal physiology.

[8]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[9]  Y. Wang,et al.  Blood oxygen saturation assessment in vivo using T2 * estimation , 1998, Magnetic resonance in medicine.

[10]  N. Hollenberg,et al.  Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition. , 1997, Kidney international.

[11]  Sean B Fain,et al.  BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction. , 2007, American journal of physiology. Renal physiology.

[12]  Fang Liu,et al.  Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. , 2012, European journal of radiology.

[13]  P. Prasad,et al.  Effect of Nitric Oxide Synthase Inhibition on Intrarenal Oxygenation as Evaluated by Blood Oxygenation Level-Dependent Magnetic Resonance Imaging , 2009, Investigative radiology.

[14]  Chris Boesch,et al.  Non‐invasive monitoring of renal oxygenation using BOLD‐MRI: a reproducibility study , 2006, NMR in biomedicine.

[15]  M. Burnier,et al.  Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. , 1993, Hypertension.

[16]  M. Kretzler,et al.  From Fibrosis to Sclerosis , 2008, Diabetes.

[17]  J. Christiansen,et al.  The effect of intravenous insulin infusion on kidney function in insulin-dependent diabetes mellitus , 1981, Diabetologia.

[18]  L. Lerman,et al.  Blood Oxygen Level–Dependent Magnetic Resonance Imaging Identifies Cortical Hypoxia in Severe Renovascular Disease , 2011, Hypertension.

[19]  R R Edelman,et al.  Noninvasive evaluation of intrarenal oxygenation with BOLD MRI. , 1996, Circulation.

[20]  S. Riederer,et al.  The use of magnetic resonance to evaluate tissue oxygenation in renal artery stenosis. , 2008, Journal of the American Society of Nephrology : JASN.

[21]  B. Lévy How to explain the differences between renin angiotensin system modulators. , 2005, American journal of hypertension.

[22]  H. Boeing,et al.  The use of biomarkers in multicentric studies with particular consideration of iodine, sodium, iron, folate and vitamin D , 2002, European Journal of Clinical Nutrition.

[23]  Chen Wang,et al.  Regulation of oxygen utilization by angiotensin II in chronic kidney disease. , 2009, Kidney international.

[24]  L. Khaodhiar,et al.  Kidney oxygenation during water diuresis and endothelial function in patients with type 2 diabetes and subjects at risk to develop diabetes. , 2004, Metabolism: clinical and experimental.

[25]  Simon L Bacon,et al.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy. , 2010, The Canadian journal of cardiology.

[26]  M. Janier,et al.  Evolution of renal oxygen content measured by BOLD MRI downstream a chronic renal artery stenosis. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[27]  Stephen J Riederer,et al.  Blood oxygen level-dependent measurement of acute intra-renal ischemia. , 2004, Kidney international.

[28]  J. Shaw,et al.  Global and societal implications of the diabetes epidemic , 2001, Nature.

[29]  M. Singer,et al.  Angiotensin II Blockade Augments Renal Cortical Microvascular pO2 Indicating a Novel, Potentially Renoprotective Action , 2003, Nephron Physiology.

[30]  F. Epstein,et al.  Changes in renal medullary pO2 during water diuresis as evaluated by blood oxygenation level-dependent magnetic resonance imaging: effects of aging and cyclooxygenase inhibition. , 1999, Kidney international.

[31]  E. Lewis,et al.  Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. , 2005, Journal of the American Society of Nephrology : JASN.

[32]  E. Porteri,et al.  Effects of candesartan cilexetil and enalapril on inflammatory markers of atherosclerosis in hypertensive patients with non-insulin-dependent diabetes mellitus , 2005, Journal of hypertension.

[33]  P. Toutouzas,et al.  Candesartan cilexetil is not associated with cough in hypertensive patients with enalapril-induced cough. Multicentre Cough Study Group. , 2000, American Journal of Hypertension.

[34]  A. Veves,et al.  Effect of diabetes on renal medullary oxygenation during water diuresis. , 2002, Diabetes care.

[35]  P. Thelwall,et al.  Non-invasive investigation of kidney disease in type 1 diabetes by magnetic resonance imaging , 2011, Diabetologia.

[36]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[37]  C. Boesch,et al.  BOLD-MRI for the assessment of renal oxygenation in humans: acute effect of nephrotoxic xenobiotics. , 2006, Kidney international.

[38]  S. Schoenberg,et al.  Renal BOLD-MRI does not reflect renal function in chronic kidney disease. , 2012, Kidney international.

[39]  M. Burnier,et al.  Renal response to the angiotensin II receptor subtype 1 antagonist irbesartan versus enalapril in hypertensive patients , 1998, Journal of hypertension.

[40]  M. Burnier,et al.  Effect of Sodium Loading/Depletion on Renal Oxygenation in Young Normotensive and Hypertensive Men , 2010, Hypertension.

[41]  Alexander G Logan,et al.  The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy , 2009 .

[42]  G. Scally Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. , 1988, BMJ.

[43]  Hans Stødkilde-Jørgensen,et al.  Validation of quantitative BOLD MRI measurements in kidney: application to unilateral ureteral obstruction. , 2005, Kidney international.

[44]  M. Burnier,et al.  Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress. , 2004, Kidney international.