(Circulation. 1996;94:3067-3068.)
© 1996 American Heart Association, Inc.
Articles |
A `BOLD' New Approach to Renal Oxygen Economy
the Department of Internal Medicine and Integrative Biology, the University of Texas Medical School at Houston.
Correspondence to Bruce C. Kone, MD, Division of Renal Diseases and Hypertension, the University of Texas Medical School at Houston, 6431 Fannin, MSB 4.148, Houston, TX 77030. E-mail bkone@heart.med.uth.tmc.edu.
Key Words: Editorials • kidney • oxygen • blood • magnetic resonance imaging • perfusion • circulation
 |
Introduction |
|---|
 Top Introduction References |
|---|
The kidney is a remarkable circulatory organ. Despite contributing <0.5% of the total body mass, the kidney commands 25% of the cardiac output and exhibits the highest rates of blood flow per weight of any organ.1 The architecture and regulatory precision of the renal microcirculation dictate large differences in blood flow among the zones of the renal parenchyma. The bulk of renal blood flow is directed to the cortex to facilitate glomerular filtration and tubular reabsorption of solute and water, whereas blood flow through the hairpin loops of the medullary vasa recta is much slower to preserve osmotic gradients necessary for efficient urinary concentration.2 The vasa recta provide nutrients and oxygen to the medullary tubules, abstract metabolic waste from the tubular reabsorbate, and help to maintain medullary interstitial osmotic gradients by acting as countercurrent exchangers. The countercurrent flow of the vasa recta, coupled with the high rates of active solute transport and gradient generation by the medullary thick ascending limb of Henle (mTAL), results in a steep corticomedullary gradient of oxygen, ranging from a PO2 of
50 mm Hg in the cortex to 10 to 20 mm Hg in the medulla.3 For decades, physiologists have been intrigued with the tenuous balance of oxygen supply and demand in the relatively hypoxic renal medulla. Indeed, the extremes of this equation for the mTAL are unparalleled among mammalian tissues and place this nephron segment at high risk for hypoxic cellular dysfunction and injury.4 5 6 Numerous studies in animals have implicated imbalances in oxygen supply and demand in the pathogenesis of acute renal failure resulting from ischemic insults, radiocontrast agents, and endogenous or exogenous nephrotoxins.6 All these physiological and pathophysiological data, and the concepts they engendered, were acquired in animals. Moreover, measurements of intrarenal oxygen tension have been made only with oxygen-sensitive microelectrodes impaled into the renal parenchyma of animals,3 methodology that is impractical and hazardous for human studies. As a consequence, the need for a noninvasive method to assess sequentially changes in the ratio of oxygen supply and demand in the kidney, particularly on a regional basis, has been critical for extension of these promising hypotheses to basic and clinical nephrological research in humans. The fact that renal medullary hypoxia and its implications for renal disease have been the subject of multiple review articles4 5 6 in prestigious medical journals, despite the lack of human data, is further testimony to the importance of this subject and the need for correlative human studies.
In the current issue of Circulation, Prasad et al7 provide the first glimpses into the regulation of intrarenal oxygenation in humans. Using the technique blood oxygenation level–dependent (BOLD) MRI, a method that exploits deoxygenated blood as an endogenous source of contrast, these authors demonstrate for the first time that the dynamics of intrarenal oxygenation can be monitored noninvasively in humans. As predicted from earlier studies with oxygen microelectrodes in anesthetized rats,3 furosemide, which inhibits active sodium reabsorption and oxygen consumption in the mTAL, increased medullary PO2 in healthy young adults, whereas acetazolamide, which principally inhibits solute reabsorption in the proximal tubules of the renal cortex, had no effect on medullary PO2. The strong correspondence of these results with the earlier animal data provides reassuring evidence that the BOLD MRI method accurately reports changes in intrarenal oxygen levels and clearly summons further inquiry into intrarenal oxygen economy in human health and disease.
BOLD MRI rests on the biophysical principle that variations in the oxygen saturation level of hemoglobin result in changes in local magnetic susceptibility and consequently MRI signal intensity.8 Oxyhemoglobin is known to be diamagnetic (zero magnetic moment caused by oxygen bound to iron), whereas deoxygenated hemoglobin is paramagnetic (magnetic moments caused by unpaired electrons—in this instance, iron).9 The magnetic susceptibility change in blood related to deoxyhemoglobin creates a locally heterogeneous magnetic environment that causes irreversible magnetic spin dephasing of blood water protons compared with the neighboring tissue; this appears as reduced signal intensity on T2*-weighted MRI images. This technique has been used principally in studies mapping brain activity in response to various tasks10 ; more recently, it has been applied to studies of myocardial perfusion.11 12 BOLD MRI offers several features that are of particular advantage to the study of regional tissue perfusion in humans. It is noninvasive, is relatively simple to perform and interpret, provides anatomic and temporal resolution unmatched by other perfusion imaging modalities, and obviates the need for potentially toxic radiocontrast agents or ionizing radiation. The rapid, repetitive acquisition of images permits dynamic assessment of net changes in tissue oxygen supply (blood flow) and consumption. As Prasad et al7 remark, the sigmoid relationship of PO2 to the oxygenation state of hemoglobin makes the BOLD MRI technique especially suited for oxygenation measurements in the hypoxic renal medulla. The technique is not without limitations; cost, combined with the inability to measure rates of blood flow and to distinguish variations in oxygen supply from changes in oxygen use, clearly constrains its utility. In addition, further refinements in spatial resolution and calibration methods for absolute quantitation of PO2 levels in the kidney will be needed to improve the value of the method.
As a research tool, BOLD MRI holds promise in further defining basic physiological mechanisms in the human kidney. The new finding of Prasad et al7 that water diuresis selectively improves medullary oxygenation in young adults provides additional evidence for a regulatory role of medullary oxygen balance in the control of both urinary concentration and dilution and invites further study of these processes. Aging is associated with a measurable loss of renal concentrating and diluting capacity,13 and one might predict from the data of Prasad et al7 that a reduced ability of the aged kidney to appropriately regulate medullary oxygenation contributes to these defects. In addition to its participation in urinary concentration and dilution, the medullary circulation plays a fundamental role in natriuresis and the maintenance of euvolemia during variations in dietary salt intake. Local production of nitric oxide appears to be a major arbiter of vasa recta and renal papillary blood flow and the pressure-induced vasodilation of the papillary circulation.14 Deficient nitric oxide synthesis or action in the renal medullary circulation has been proposed to contribute to the pathological salt retention in some forms of hypertension. BOLD MRI should facilitate studies of the adaptive and maladaptive responses of the medullary circulation to chronic volume expansion in humans and should prove useful in testing mechanistically specific interventions (such as administration of the nitric oxide substrate L-arginine) aimed at promoting natriuresis.
In the outer medulla, ischemia promotes swelling of endothelial and tubular cells and neutrophil adherence to microvessels.6 The resulting vascular congestion reduces blood flow and oxygen supply to the medulla, tipping the balance to a state of oxygen insufficiency. Consequently, a number of therapeutic strategies to improve medullary blood flow and oxygenation after ischemic renal insults have been proposed and tested in animal models. An impressive body of in vitro and in vivo data in animals suggests that restoring the balance of oxygen supply and tubular workload in the injured renal medulla improves renal functional outcome. For example, infusion of a cGMP-phosphodiesterase inhibitor dramatically improved medullary blood flow and ameliorated renal failure in rats subjected to acute renal ischemia.15 Similarly, administration of neutralizing antibodies16 or antisense oligonucleotides17 directed against intercellular adhesion molecule 1 reduced medullary vascular congestion by neutrophils and dramatically improved renal outcome in rat models of acute renal ischemia. BOLD MRI should prove useful in determining whether these or other therapies effectively improve medullary oxygen dynamics in humans and whether restoration of premorbid medullary oxygenation correlates with improved renal outcome. One can easily envision a time when the goal of initial therapy of ischemic renal injury is to achieve a target level of medullary PO2, as measured by BOLD MRI, that limits injury and hastens recovery. Conceivably, this method might also serve as an adjunctive aid in estimating the severity of renal injury early in its course, predicting both potential reversibility and response to therapy of renal injury, elucidating mechanisms of nephrotoxicity of new and existing drugs, and identifying with greater sensitivity those patients at high risk for ischemic or nephrotoxic renal injury; failure to increase medullary PO2 in response to furosemide, for example, might represent a positive renal "stress test." Of course, for BOLD MRI to gain widespread clinical application, it must demonstrate increased diagnostic sensitivity and specificity over current methods and must reliably predict responses to therapy. Considerable research will be needed for BOLD MRI to achieve such promise.
|
Acknowledgments |
|---|
This work is supported by NIH grant DK-47981 and an Established Investigator Award from the American Heart Association.
|
Footnotes |
|---|
The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Beeuwkes R III. The vascular organization of the kidney. Annu Rev Physiol. 1980;42:531-542.[Medline] [Order article via Infotrieve]
2. Michel CC. Renal medullary microcirculation: architecture and exchange. Microcirculation. 1995;2:125-139.[Medline] [Order article via Infotrieve]
3.
Brezis M, Agmon Y, Epstein FH. Determinants of intrarenal oxygenation, I: effects of diuretics. Am J Physiol. 1994;267:F1059-1062.
4. Brezis M, Rosen S, Silva P, Epstein FH. Renal ischemia: a new perspective. Kidney Int. 1984;26:375-383.[Medline] [Order article via Infotrieve]
5.
Brezis M, Rosen S. Hypoxia of the renal medulla: its implications for disease. N Engl J Med. 1996;332:647-655.
6.
Thadhani R, Pascuel M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334:1448-1460.
7.
Prasad PV, Edelman RR, Epstein FH. Noninvasive evaluation of intrarenal oxygenation with BOLD MRI. Circulation. 1996;94:3271-3275.
8. Thulborn KR, Waterton JC, Matthews PM, Radda GK. Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta. 1982;714:265-270.[Medline] [Order article via Infotrieve]
9.
Pauling L, Coryell CD. The magnetic properties and structure of hemoglobin, oxyhemoglobin, and carbonmonoxyhemoglobin. Proc Natl Acad Sci U S A. 1936;22:210-216.
10.
Ogawa S, Tank TW, Menon R, Ellermann, Kim SG, Mekle H, Ugurbil K. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A. 1993;89:5951-5955.
11. Niemi P, Poncelet BP, Kwong KK, Weisskoff RM, Rosen BR, Brady TJ, Kantor HL. Myocardial intensity changes associated with flow stimulation in blood oxygenation sensitive magnetic resonance imaging. Magn Res Med. 1996;36:78-82.[Medline] [Order article via Infotrieve]
12. Li D, Dhawale P, Rubin PJ, Haacke EM, Gropler RJ. Myocardial signal response to dipyridamole and dobutamine: demonstration of the BOLD effect using a double-echo gradient-echo sequence. Magn Res Med. 1996;36:16-20.[Medline] [Order article via Infotrieve]
13. Lindeman RD, Lee TD, Yiengst MJ, Shock NW. Influence of age, renal disease, hypertension, diuretics and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. J Lab Clin Med. 1968;68:206-223.
14.
Cowley AG, Mattson DL, Lu S, Roman RJ. The renal medulla and hypertension. Hypertension. 1995;25:663-673.
15. Guan A, Miller SB, Greenwald JE. Zaprinast accelerates recovery from established acute renal failure in the rat. Kidney Int. 1995;47:1569-1575.[Medline] [Order article via Infotrieve]
16.
Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A. 1994;91:812-816.
17. Haller H, Dragun D, Miethke A, Park JK, Weis A, Lippoldt A, Grob V, Luft FC. Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat. Kidney Int. 1996;50:473-480.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Pedersen, Z. Vajda, H. Stodkilde-Jorgensen, S. Nielsen, and J. Frokiaer Furosemide increases water content in renal tissue Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1645 - F1651. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||