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Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m2/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression. Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m2/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression. Chronic kidney disease (CKD) is a major public health problem.1Astor B.C. Matsushita K. Gansevoort R.T. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.Kidney Int. 2011; 79: 1331-1340Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar Diabetes, arterial hypertension (AH), and proteinuria are well-known risk factors for disease progression, but predicting the evolution of CKD remains a difficult task. For incompletely understood reasons, the glomerular filtration rate (GFR) of some CKD patients will hardly decrease over the years, whereas in others, it will rapidly progress toward end-stage renal disease. The early identification of CKD patients at risk of progressive renal function decline (progressors) would allow a more focused distribution of health care resources and improved planning of renal replacement methods. However, a multitude of circulating or urinary biomarkers has been proposed to predict outcome, so far with inconsistent results.2Shlipak M.G. Day E.C. Biomarkers for incident CKD: a new framework for interpreting the literature.Nat Rev Nephrol. 2013; 9: 478-483Crossref PubMed Scopus (29) Google Scholar Renal tissue hypoxia is considered as the common final pathway in the development and progression of CKD, irrespective of its cause.3Fine L.G. Norman J.T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.Kidney Int. 2008; 74: 867-872Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar Animal studies have provided evidence of this hypothesis, yet data in humans were limited for a long time due to the lack of a method to assess renal tissue oxygenation noninvasively in humans. This situation has changed thanks to the development of blood oxygenation level–dependent magnetic resonance imaging (BOLD-MRI).4Prasad P.V. Edelman R.R. Epstein F.H. Noninvasive evaluation of intrarenal oxygenation with BOLD MRI.Circulation. 1996; 94: 3271-3275Crossref PubMed Scopus (354) Google Scholar In brief, BOLD-MRI uses the paramagnetic properties of deoxyhemoglobin to assess tissue oxygenation: the higher the local deoxyhemoglobin levels are, the higher the so-called apparent relaxation rate R2* (s−1) is and the lower local tissue oxygen content is, assuming that blood po2 is in equilibrium with tissue po2. BOLD-MRI is performed without contrast and therefore is an ideal method for patients with CKD. Standardization of the examinations and refinements in the methods to analyze the images has resulted in a reproducible technique with low interobserver variability.5Pruijm M. Milani B. Burnier M. Blood Oxygenation Level-Dependent MRI to Assess Renal Oxygenation in Renal Diseases: Progresses and Challenges.Front Physiol. 2016; 7: 667PubMed Google Scholar Recent BOLD-MRI studies have demonstrated that the R2* values of renal parenchyma are higher in CKD patients, suggesting lower renal tissue oxygenation.6Thacker J.M. Li L.P. Li W. et al.Renal Blood Oxygenation Level-Dependent Magnetic Resonance Imaging: A Sensitive and Objective Analysis.Invest Radiol. 2015; 50: 821-827Crossref PubMed Scopus (24) Google Scholar, 7Prasad P.V. Thacker J. Li L.P. et al.Multi-Parametric Evaluation of Chronic Kidney Disease by MRI: A Preliminary Cross-Sectional Study.PLoS One. 2015; 10e0139661Crossref PubMed Scopus (44) Google Scholar, 8Milani B. Ansaloni A. Sousa-Guimaraes S. et al.Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging.Nephrol Dial Transplant. 2017; 32: 2097-2105PubMed Google Scholar Differences in R2* between CKD patients and healthy controls have been mainly reported in the cortex, whereas medullary oxygenation seems relatively well preserved at a lower GFR. Acute decreases in medullary R2* levels have been described after the administration of furosemide and are greater in young persons with preserved renal function compared with older persons or patients with CKD.9Epstein F.H. Prasad P. Effects of furosemide on medullary oxygenation in younger and older subjects.Kidney Int. 2000; 57: 2080-2083Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 10Pruijm M. Hofmann L. Piskunowicz M. et al.Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.PLoS One. 2014; 9e95895Crossref PubMed Scopus (69) Google Scholar The effect of furosemide has been explained by the fact that it blocks the Na+-K+-2Cl− transporter in the thick ascending loop of Henle, will acutely decrease oxygen-consuming active sodium transport, and increase local po2.11Liss P. Nygren A. Ulfendahl H.R. et al.Effect of furosemide or mannitol before injection of a non-ionic contrast medium on intrarenal oxygen tension.Adv Exp Med Biol. 1999; 471: 353-359Crossref PubMed Google Scholar BOLD-MRI combined with i.v. furosemide is therefore considered by many as a functional test: the greater the change is in R2*, the more functional tubuli that are still present.12Gomez S.I. Warner L. Haas J.A. et al.Increased hypoxia and reduced renal tubular response to furosemide detected by BOLD magnetic resonance imaging in swine renovascular hypertension.Am J Physiol Renal Physiol. 2009; 297: F981-F986Crossref PubMed Scopus (45) Google Scholar To the best of the reported BOLD-MRI studies were or and it remains therefore whether renal tissue hypoxia baseline R2* or in R2* predict renal function decline in humans. The of this study was therefore to assess whether renal tissue oxygenation as measured with BOLD-MRI is associated with renal function decline in a of CKD patients, hypertensive patients without CKD, and A baseline was performed in CKD patients, hypertensive patients, and healthy were due to the to BOLD-MRI or other for patients were of A of hypertensive patients and controls not to for a and were therefore of the are in In the CKD patients hypertensive and of the measured and arterial are in of BOLD-MRI of a healthy and a CKD is in for on other of CKD, baseline estimated and BOLD-MRI to the of CKD are provided in of CKD patients, hypertensive patients, and sodium arterial analysis of blood CKD, chronic kidney eGFR, estimated glomerular filtration in a new and arterial to resonance imaging R2* mean R2* of the cortical layers of renal R2* mean R2* of the to layer to of renal R2* slope R2* R2* the change in R2* of the layers after i.v. 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The outer R2* values of the CKD patients with renal function decline over time to after years, whereas change in the CKD patients without renal function decline to To the best of this is the of an between renal tissue hypoxia and renal function decline in humans. we that the lower the oxygenation of the to high R2* is, the the yearly decline of the In this renal tissue oxygenation was associated with renal CKD patients with the cortical oxygenation were times more likely to a major renal for renal replacement therapy or an increase of in baseline serum with preserved renal tissue The R2* slope, on the R2* values but on was associated with renal function decline and renal a slope to a greater yearly decline in renal function and In we not between the change in medullary R2* values as at baseline and the eGFR decline. A of renal as a major of renal disease progression was proposed by et L.G. Norman J.T. renal disease: the chronic hypoxia Google Scholar in The so-called chronic hypoxia hypothesis that of to of The local and to and renal function a This hypothesis has been by many K. M. et of tubular hypoxia in the early in the kidney Nephrol. PubMed Scopus Google Scholar, J.T. M. et renal cortical a Physiol. 94: PubMed Scopus Google Scholar yet evidence in humans was still The of this prospective study BOLD-MRI to assess renal tissue oxygenation the of chronic tissue hypoxia in CKD development and progression in humans. between baseline renal R2* eGFR and adverse renal outcome were to the more cortical layers of the renal and was between eGFR decline or renal outcome and baseline R2* values of medullary This is in with BOLD-MRI from and other that but not oxygenation is in P.V. Thacker J. Li L.P. et al.Multi-Parametric Evaluation of Chronic Kidney Disease by MRI: A Preliminary Cross-Sectional Study.PLoS One. 2015; 10e0139661Crossref PubMed Scopus (44) Google Scholar, 8Milani B. Ansaloni A. Sousa-Guimaraes S. et al.Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging.Nephrol Dial Transplant. 2017; 32: 2097-2105PubMed Google Scholar The cortical hypoxia explained by the of a in cortical blood and glomerular in and reduced of tubular as in P. et al.Determinants of kidney oxygen and to tissue oxygen in and Exp Physiol. 2013; PubMed Scopus Google Scholar tubular are the in the are the tubular a of with Therefore, are to in L.G. Norman J.T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.Kidney Int. 2008; 74: 867-872Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar whereas in renal blood mainly at the cortical in of J.M. et MRI is to early in 2017; PubMed Scopus Google Scholar, A. B. et in glomerular filtration rate after renal with and in renal PubMed Scopus Google Scholar this cortical oxygenation has a greater impact on eGFR decline medullary blocks active sodium in and to an decrease in oxygen in the have that the BOLD-MRI response to furosemide as a to assess renal function response to furosemide a of tubular functional in and humans with renal disease for to renal L.G. Norman J.T. renal disease: the chronic hypoxia Google Scholar, J.A. et oxygen level-dependent magnetic resonance imaging cortical hypoxia in renovascular 2011; PubMed Scopus Google Scholar In this we the of renal oxygenation after the administration of furosemide as a of renal function decline. Thus, BOLD-MRI was after the administration of furosemide in and the in R2* were analyzed in each of the 12 in R2* were greater in medullary layers and greater in healthy as reported M. Hofmann L. Piskunowicz M. et al.Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.PLoS One. 2014; 9e95895Crossref PubMed Scopus (69) Google Scholar in by furosemide were in CKD patients, likely due to the fact that have functional tubuli of renal but the tubular of is for its is reduced in CKD. However, we not between the change in R2* and eGFR decline or the of the furosemide as a predictor of renal function decline in to the of the with the of the layers, as with the concentric objects likely cortical This have the effect of furosemide and the lack of of the furosemide In the R2* slope was associated with eGFR decline and an adverse renal This is for it is that the R2* values are by M. Milani B. Burnier M. Blood Oxygenation Level-Dependent MRI to Assess Renal Oxygenation in Renal Diseases: Progresses and Challenges.Front Physiol. 2016; 7: 667PubMed Google Scholar, A. K. J. et the between renal and renal tissue an of magnetic resonance imaging and Radiol. 2014; PubMed Scopus Google Scholar and this of The R2* slope this it on the distribution and on the R2* studies are to this and to assess the of the R2* slope in a A of a or to assess whether in renal tissue oxygenation that the R2* values not change over was a toward higher outer R2* values over time CKD patients with a decline in The of R2* values over time in hypertensive patients and controls the of BOLD-MRI performed In this finding that with reduced renal tissue oxygenation at baseline over long of in to the as by the chronic hypoxia This study in the of its and its are the prospective the of a control the of a and a reproducible method of BOLD-MRI A is the lack of a to is to studies in this the technique with from renal has in its to predict the decline in renal function over this study for the time between renal tissue oxygenation and eGFR decline and that renal tissue oxygenation is an in CKD progression, the chronic hypoxia This study the to studies exploring functional MRI as a to new therapeutic that renal disease progression. However, still to BOLD-MRI is not and remains the has not been as by the the of BOLD-MRI to from is is an and to assess the renal risk in the of the proteinuria with BOLD-MRI the that the development of renal MRI that MRI as arterial and imaging will to predict renal outcome MRI P.V. Thacker J. Li L.P. et al.Multi-Parametric Evaluation of Chronic Kidney Disease by MRI: A Preliminary Cross-Sectional Study.PLoS One. 2015; 10e0139661Crossref PubMed Scopus (44) Google Scholar, P. P. et of intrarenal and oxygen Exp Physiol. 2013; PubMed Scopus Google Scholar This will to a and identification of CKD patients at the risk of end-stage renal disease. This was by the local of the and to the of the of was obtained from Patients with CKD or with without CKD at the of the and at the of were for this CKD was as an eGFR or the of irrespective of its et and of chronic kidney disease: a from Kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar, J. et serum creatinine values in the of in renal disease study for glomerular filtration PubMed Scopus Google Scholar was as a mean blood measured on more or an blood or more patients to to at and to the study A healthy control was were by local and were healthy individuals without a of kidney disease or other and without renal on a for were years, a to MRI as or the of a or other or the of with a CKD patients not were on renal replacement a kidney or kidney the to the K. J.A. in the risk and Int. 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Pruijm et al. (Tue,) studied this question.