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Kidney oxygenation under pressure
van der Bel, R.
Publication date
2017
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van der Bel, R. (2017). Kidney oxygenation under pressure.
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Chapter
1
Introduction and thesis outline
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introduction
Chronic kidney disease (CKD) is characterized by a progressive decrease of the kidney’s filtra-tion capacity – i.e. the glomerular filtration rate (GFR) – with or without increased urinary
excretion of albumin. It is an increasing public health issue, with an estimated worldwide
prevalence of 8 to 16% in 2013
1. Hypertension together with diabetes mellitus are the lead-ing causes of CKD and ultimately end-stage renal failure when renal replacement therapy via
either dialysis and/or kidney transplantation are the only therapeutic options remaining
1,2.
Cardiovascular disease is the most common cause of death among CKD patients
3,4. In fact
hypertension is not only a causal factor in CKD, it is a consequence as well and blood pres-sure management is often difficult in these patients
5.
Thus, hypertension is a highly prevalent and relevant comorbidity in CKD. There is substan-tial evidence that nephrogenic hypertension can be attributed to increased sympathetic
nerve activity (SNA) in these patients
6-9. However, the mechanisms underlying increased
SNA in CKD are not completely understood. Several studies have reported an attenuation of
SNA and blood pressure following bilateral nephrectomy
10-12. This has founded the concept
that the trigger of the enhanced central sympathetic outflow in CKD patients resides in the
affected kidneys themselves. Deterioration of renal oxygenation by altered renal perfusion
and increased metabolic demand has been postulated as a common factor in the progres-sion of CKD
13-17and nephrogenic sympathetic hyperactivity and hypertension
6,18,19. This has
led to the conceptual framework depicted in Figure 1.
Figure 1 Conceptual framework of blood pressure regulation and kidney
hypoxia in the progression of chronic kidney disease. The color-coded items and paths are investigated the different chapters of this thesis. Green is chapter 2, blue chapter 3, red chapter 4 and orange chapter 5.
| Chapter 1 | 10
In summary this concept holds kidney metabolism at the center and shows how the sympa-thetic nervous system and renin angiotensin system (RAS) may affect kidney perfusion and
metabolic load, leading to kidney hypoxia and disease progression (i.e. nephrosclerosis). At
first, this concept may sound surprising considering the kidneys together receive about 20%
of cardiac output
20, which is more than any other organ including the brain. Thus, sufficient
oxygen should be available. However, in order for the kidneys to function properly a steep
osmotic gradient needs to be applied from the outer to the inner medulla to aid resorption of
solutes from the pre-urine. To maintain this gradient the blood perfusion in this area needs
to be tightly regulated, while simultaneously the most metabolic demanding processes take
place in the outer medulla. This results in a steep oxygen gradient in the medulla making the
kidneys susceptible to hypoxia
21,22. According to the conceptual framework at hand, early
oxygenation dysregulation then easily transients further into hypoxia due to negative feed-back loops present in the system (Fig. 1 circular arrows). This framework also founded the
rationale for catheter based renal denervation as potential antihypertensive treatment
23,24.
Described in Figure 1 is the conceptual framework as it was, at the on-set of the studies
presented in this thesis. It shows the central role of the sympathetic nervous system and the
renin angiotensin system in regards to blood pressure regulation and their effect on tubular
oxygen consumption and medullar perfusion. However, at the outset of these studies several
conceptual caveats remained, regarding:
Kidney function Each kidney – containing about 1 mil-lion nephrons (see figure) – receives about 600 mL of blood per minute. Almost all blood passes through the glomeruli, where it is filtered. This is a passive process, as the vessel wall acts as a sieve, the local pressure inside the glomerular capillaries is regulated and de-termines the amount of filtrate, or pre-urine, that is produced. This is the Glomerular Filtration Rate (GFR). The total amount of blood plasma that passes through the kidneys’ glomeruli is the Effective Renal Plasma Flow (ERPF) and the ratio of the filtrate to the total plasma flow is the Filtration Fraction (FF). Thus, with an average FF ~20%, about 175 liters of pre-urine is produced daily.Almost all pre-urine is resorbed in the tubuli (i.e.
~99%). Part of this process, sodium resorption in particular, requires oxygen. In most organs an increase in oxygen demand is simply resolved by increasing blood flow. However, kidney oxygenation is unique as an in-crease in blood supply leads to more urine production, requiring higher resorption rates and thus increases oxygen demand 25,26.
Figure: Cancer Research UK / Wikimedia Commons (2015, 8 December).§
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1. the uniqueness of the sympathetic dysregulation in CKD patients (Figure 1 in green).
2. the effect of hyperoxia on blood pressure (Figure 1 blue path)
3. the link between RAS, SNA and kidney hypoxia in humans, (Figure 1 orange and red
paths).
In this thesis we put the conceptual framework under pressure to test these paths and fea-tures and developed the methods to do so, i.e. to minimally invasive assess renal perfusion
and oxygenation in humans.
Sympatho-vagal balance and cardio-metabolic impairment
Sympathetic hyperactivity is not merely present in CKD, it is common in many
cardio-metabolic diseases. Therefore, before we study its role in kidney disease we need to explore
its epidemiology. Sympathetic hyperactivity is a form of autonomic dysregulation that is
characterized by a decreased arterial baroreflex function, amongst other characteristics. As
changes in the arterial blood pressure are detected at baroreceptors in the aortic arch and
carotid sinuses – i.e. sensory input to the (cardiovascular) autonomic nervous system – the
autonomic nervous system acts to adjust the arterial pressure by altering the heart rate and/
or the myocardial contractility, as well as the systemic vascular resistance. Alterations in the
sensitivity of this mechanism to blood pressure changes can be quantified by measurement
of the baroreflex sensitivity. This has already been established as an important determinant
of the sympatho-vagal balance of the cardiovascular system
27. Baroreflex dysfunction is
common in cardio-metabolic disease and BRS has been shown to be a clinically relevant and
independent prognostic factor in cardiovascular disease, hypertension, metabolic syndrome
and obesity, amongst others
28-35.
This wide range in applicability of BRS indicates a potential as an integrative risk factor for
cardiovascular disease, that may be especially relevant to kidney disease patients. In
Chap-ter 2 we therefore investigated the BRS in a large population study to evaluate and explore
its associations between with cardiovascular risk factors and cardio-metabolic impairment.
The effect of hyperoxia on blood pressure in CKD patients
All visceral organs contain peripheral chemoreceptors, which communicate their signal to
the autonomic nervous system upon activation, whereby they can directly influence cardiac
and respiratory function (Figure 1, blue pathway). Among these receptors there are those
sensitive to hypoxia that induce sympathetic activity, once activated. Various groups have
found altered renal chemoreceptor activation in CKD
36-38. The proof of concept was provided
by a study by Hering et al. who exposed CKD patients to 100% oxygen over a non-rebreathing
mask for 15 min. This resulted in a 30% reduction in SNA accompanied by a lower pulse pres-sure
37. As this response was absent in healthy controls and non-CKD patient populations
39,40,
| Chapter 1 | 12
the observed effects on sympathetic nerve activity and blood pressure were attributed to
CKD-specific hypoxia mediated renal chemo-reflex deactivation. Additional support for the
existence of a kidney-derived chemo-reflex, were the observations in non-CKD sympatheti-cally hyperactive patient groups not showing such a response
41,42.
Thus, the hemodynamic response to oxygen supplementation appears to be uniquely
different in CKD patients. However, these studies did not show the mechanism by which
oxygen supplementation reduced SNA activity in CKD patients. Considering the conceptual
framework described above (Fig. 1), sympathetic deactivation must lead to vasodilatation
to lower blood pressure. Therefore we repeated the experiments by Hering et al
37, while
including steps to measure the dose effect of the oxygen supplementation and include
measurements of systemic vascular resistance and baroreflex function. For this study we
literally put CKD patients under pressure in the hyperbaric chamber facility. The results are
described in
Chapter 3.
MRI in a nutshell MRI scanners use the
mag-netic properties of hydrogen atoms in the body. The nucleus of each hydrogen atom consists of one spinning proton, that thereby generates a tiny magnetic field. In the powerful MRI magnet these protons align and can be excited to change their orientation by sending resonating radio fre-quent (RF) signals into the body. When returning to their original position these protons act as tiny magnets ‘echoing’ the radio frequent signal, that is picked up by receiver coils. During this process the protons are affected by their surroundings, changing the magnitude of their ‘echo’. This is
unique to every substance (e.g. water, fat, bone etc.), this is what creates the contrast in MRI images. How-ever, some of the disturbances are unwanted, such as motion (e.g. moving blood) or magnetically active substances (e.g. metal). While this can negatively affect standard MRI imaging, these disturbances can also be exploited to generate other contrasts in the eventual image.
Photograph: 3 Tesla MRI at the AMC-UvA
Angiotensin-II and kidney oxygenation using functional MRI of the kidney
Kidney oxygenation can reliably be assessed by blood oxygen level dependent (BOLD)
MRI
43,44. As BOLD MRI is sensitive to the blood deoxyhemoglobin level, the acquired signal
is the composite result of oxygen extraction from the blood (i.e. metabolic demand) and the
rate of oxygen delivery (i.e. perfusion)
45. The technique was originally validated in a porcine
model
46. Also, in subsequent human studies the technique was shown to provide excellent
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Although BOLD MRI can track intra-individual changes in oxygenation, researchers have
found only limited associations between kidney oxygenation measured by blood oxygen level
dependent (BOLD) MRI and kidney function measured by estimated glomerular filtration
rate (eGFR)
47,48. The GFR denotes the amount of fluid that is filtered through the glomerular
filtration membrane in the kidney and is a measure of the filter performance and capacity
of the kidneys. In CKD the GFR slowly declines due to gradual loss of nephrons. Therefore
the GFR is used as a primary measure of disease progression in CKD. Also, GFR indirectly
represents the kidney’s metabolic demand. The more blood is filtered (high GFR) the more
water and solutes need to be resorbed, which is energy demanding. Thus, the kidney is
unique compared to other organs in such a way that an increase in perfusion increases the
GFR and thereby increases in metabolic demand as well. These unique attributes need to be
taken into account in the interpretation of kidney MRI.
Therefore we propose that kidney oxygenation status is reflected by the perfusion (i.e. oxy-gen supply) to GFR (i.e. oxygen demand) ratio, which is the filtration fraction. The filtration
fraction denotes the amount of pre-urine formed per amount of blood that passes through
the kidneys. Thus, to relate kidney BOLD MRI to kidney function measure by GFR, the BOLD
MRI measurement needs to be corrected for the kidney’s perfusion. This can be done using
phase contrast MRI, which is a sequence sensitized to quantify motion by measuring the
phase shift in the MRI signal. Using this technique we can measure the velocity of blood
flowing through the renal artery and calculate the renal artery blood flow.
To investigate the added value of phase contrast MRI renal blood flow measurements to
kidney BOLD MRI we performed an experiment using angiotensin II infusions in healthy sub-jects. The renin-angiotensin-aldosterone system (RAAS) is responsible for regulation of the
arterial blood pressure in the long-term. This system is regulated by the kidney to compen-sate for loss in effective circulating volume by activating angiotensin II, a potent arteriolar
vasoconstrictor. Activation of angiotensin II is of major consequents to kidney perfusion
and oxygenation itself
49,50. Angiotensin-II predominantly provides vasoconstriction of the
efferent glomerular arteriole. Kidney perfusion is thereby decreased while simultaneously
the filtration pressure in the glomeruli is increased, thereby raising the filtration fraction
Blood Oxygen Level Dependent
MRI exploits the magnetic properties of deoxy- hemoglobin. By measuring signal decay over time, the amount of deoxyhemo-globin can be estimated. Whereby, fast decay means a lot of deoxyhemoglobin is present and the tissue oxygenation is low and vice versa. Thus, BOLD MRI indicates the local hemoglobin oxygen saturation and therefore, oxygenation (reflected by BOLD MRI) is a balance or competition between oxygen supply (blood perfusion) and oxygen extraction from the blood (metabolic demand).
| Chapter 1 | 14
(Figure 2, red pathway). A previous study by Schachinger et al showed an acute decrease in
cortical oxygenation during bolus injections of angiotensin II (Ang-II) in healthy humans
51.
Additionally, other studies showed that blocking the RAAS in CKD patients increases renal
oxygenation
52-54.
Thus angiotensin-II infusion should put kidney oxygenation under pressure. The result of
these studies are described in
Chapter 4. There we also use gold standard radio isotope
kidney function tests to assess the associations between kidney function, perfusion and
oxygenation.
Direct effect of sympathetic activity on kidney oxygenation not shown in
humans
The link between SNA and renal hypoxia has primarily been investigated in animal models
using invasive measurement techniques that cannot be applied in humans. These studies
found that kidney sympathetic activation decreases renal blood flow
61. Simultaneously,
sympathetic nerves directly innervate the renal tubules inducing sodium reabsorption and
thereby increasing metabolic demand
62,63. The net effect of which is a decreased renal blood
flow and increased tubular demand is therefore a decrease in oxygenation (Figure 1, orange
pathway)
16,62,63. However, in humans direct observations of the effect of sympathetic activa-tion on kidney oxygenation are lacking.
Lower Body Negative Pressure (LBNP) can be used to experimentally increase systemic SNA
in humans
55,56,64. LBNP is therefore ideally suited to investigate the sympatho-renal effects
on kidney oxygenation. In
Chapter 5 we describe the use of LBNP in an MRI scanner during
Lower Body Negative Pressure is a technique
used to induce sympathetic activity in humans in a controlled experimental setting. It consists of a container that is placed around a subject’s legs and is sealed around the waist. Then a vacuum can be applied inside this container to a certain level, whereby drawing blood towards the pelvic region and legs and generating hypovolemia (top figure). Low-grade LBNP induces sustained sympa-thetic activation without systemic blood pressure effects 55. Moderate-grade LBNP induces further
sympathetic activation with moderate hemody-namic effects, while maintaining organ perfusion pressure 56-58. In the kidneys, LBNP reduces blood
flow and glomerular filtration rate while glomeru-lar filtration fraction (FF) remains unaffected 4,58-60.
Photograph: LBNP box on the MRI table at the
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multimodal functional MRI to evaluate kidney perfusion and oxygenation during increasing
sympathetic activity by in healthy humans.
Kidney specific intravoxel incoherent motion analysis
A major drawback of any MRI based perfusion measurements – including phase contrast
MRI – is their inability to discriminate between blood and urine perfusion. To overcome this
problem we included a diffusion weighted imaging (DWI) sequence optimized for kidney
specific intravoxel incoherent motion (IVIM) analysis. Using this method we show its ability
to detect and follow changes in kidney perfusion. Not only blood perfusion, but urine perfu-sion as well.
The DWI sequence is not only sensitive Brownian motion, but to any form of motion in-cluding that caused by perfusion. However, the higher the magnitude of the gradient pulse
the less sensitive the signal is to fast perfusion motion. By introducing additional gradient
pulses at low b-values, the proportion of fast bulk motion to slow Brownian motion can be
quantified. This is the basis of IVIM analysis. IVIM analysis of employs a bi-exponential decay
model to distinguish between capillary perfusion and tissue diffusion fractions
65,66. Since
its introduction, IVIM modelling has been applied to human kidneys, e.g. to identify altered
perfusion in native kidney lesions and hypo-perfused regions in transplanted kidneys
67-71.
However, as Muller et al
67already noticed, the kidneys are rheologically more complex than
other organs and a bi-exponential model may not be sufficient to model renal physiology.
Incorporating a third exponent in the IVIM model could solve this problem. Such a model
could enable discrimination between blood and pre-urine flow. Recently, it was shown by Van
Baalen et al
72that such a tri-exponential IVIM model may be preferable in the kidney. In their
implementation, the tri-exponential model produced three distinct signal fractions: a diffu-sion fraction, an intermediate bulk motion fraction (f
i) and a fraction of fast bulk motion (f
f).
These fractions were shown to be consistent with the distinct functional regions within the
kidney
72. However, it remains unclear how this model relates to changes in kidney perfusion.
Diffusion Weighted Imaging MRI can be sensitized to diffusion by introducing a
linear variance in the magnetic field using a pulsed field gradient. As the precession frequency of protons is proportional to the magnetic field strength, the orienta-tion of the proton spins will change at different rates. This results in dispersion of the spin phase and loss of signal. If then a gradient pulse is applied of the same magnitude but opposite direction, the proton spins will start to refocus or rephase. However, the result of this refocusing will not be perfect for protons that have moved during the pulse interval and the measured signal is reduced. This reduc- tion is proportional to speed and distance of proton movement. Thus, dense tis-sues will only allow little diffusion (Brownian motion) and thus show a high signal after phase refocusing and vice versa.
| Chapter 1 | 16
In
Chapter 6 we describe our findings using the tri-exponential approach to IVIM analysis
in relation to perfusion changes caused by Ang-II infusion and relate the shifts in perfusion
fractions to changes in gold standard measured GFR and renal plasma flow. This approach
may provide a MRI based method that can simultaneously quantify and map shifts in kidney
perfusion and filter function, to identify hyper filtration.
outline of this thesis
Blood pressure regulation is disturbed not only in kidney disease patients, but in most
cardio-metabolic disease. It may even be an early integrative marker for cardiovascular
disease. Therefore, in
Chapter 2, BRS is evaluated in the HELIUS cohort to explore BRS in a
large relatively healthy population.
In
Chapter 3 we investigate whether oxygen supplementation can reduce blood pressure
in CKD patients. A session of hyperbaric oxygen was part of this study. In
Chapter 3B we
describe the conversion of a Portapres® device for use under hyperbaric conditions.
Evaluation of kidney hypoxia in humans is not possible using traditional kidney function
measurements.
Chapter 4 describes the use of MRI techniques to evaluate kidney perfusion
and oxygenation while depressed by Angiotensin II infusion to induce kidney hypoxia. There
we compare these results to gold standard radioisotope kidney function tests.
In
Chapter
5 we apply multimodal functional MRI to evaluate kidney perfusion and oxy-genation during increased sympathetic activity by lower body negative pressure in healthy
humans.
A different approach to measure tissue perfusion is the application of Intravoxel Incoherent
Motion (IVIM) analysis. The study described in Chapter 4 included DWI sequences optimized
to investigate whether a kidney specific tri-exponential approach to IVIM is able to detect
and follow changes in kidney perfusion. Not only blood perfusion, but urine perfusion as
well. Our findings using this technique are described in
Chapter 6.
In
Chapter 7 the results of the studies are discussed in respect to one another and other
recent research in the field to assess how the conceptual framework holds up and how this
information may be of consequence to science and clinic in the future. Specific recommen-dations are made on how to improve and apply multi modal MRI of the kidneys for clinical
research and possibly implementation.
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references
1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives.
Lancet. 2013; 382(9888): 260-272.
2. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012; 379(9811): 165-180.
3. Sarnak MJ. Cardiovascular complications in chronic kidney disease. American journal of kidney
dis-eases : the official journal of the National Kidney Foundation. 2003; 41(5 Suppl): 11-17.
4. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013; 382(9889): 339-352.
5. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll
Cardiol. 2008; 52(22): 1749-1757.
6. Converse RL, Jr., Jacobsen TN, Toto RD, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992; 327(27): 1912-1918.
7. Koomans HA, Blankestijn PJ, Joles JA. Sympathetic hyperactivity in chronic renal failure: a wake-up call. J Am Soc Nephrol. 2004; 15(3): 524-537. 8. Neumann J, Ligtenberg G, Klein II, et al. Sympathetic hyperactivity in chronic kidney disease: patho-genesis, clinical relevance, and treatment. Kidney Int. 2004; 65(5): 1568-1576. 9. Herzog CA, Mangrum JM, Passman R. Sudden cardiac death and dialysis patients. Semin Dial. 2008; 21(4): 300-307. 10. Medina A, Bell PR, Briggs JD, et al. Changes of blood pressure, renin, and angiotensin after bilateral nephrectomy in patients with chronic renal failure. Br Med J. 1972; 4(5842): 694-696. 11. Getts RT, Hazlett SM, Sharma SB, et al. Regression of left ventricular hypertrophy after bilateral ne-phrectomy. Nephrol Dial Transplant. 2006; 21(4): 1089-1091.
12. Gawish AE, Donia F, Fathi T, et al. It takes time after bilateral nephrectomy for better control of resis-tant hypertension in renal transplant patients. Transplant Proc. 2010; 42(5): 1682-1684. 13. Fine LG, Bandyopadhay D, Norman JT. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int Suppl. 2000; 75: S22-26. 14. Fine LG, Orphanides C, Norman JT. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl. 1998; 65: S74-78. 15. Eckardt KU, Bernhardt WM, Weidemann A, et al. Role of hypoxia in the pathogenesis of renal disease.
Kidney Int Suppl. 2005(99): S46-51.
16. Evans RG, Ince C, Joles JA, et al. Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology. Clin Exp Pharmacol Physiol. 2013; 40(2): 106-122.
17. Hansell P, Welch WJ, Blantz RC, et al. Determinants of kidney oxygen consumption and their relation-ship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol. 2013; 40(2): 123-137. 18. Hausberg M. Sympathetic Nerve Activity in End-Stage Renal Disease. Circulation. 2002; 106(15): 1974-1979. 19. Siddiqi L, Joles JA, Grassi G, et al. Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? J Hypertens. 2009; 27(7): 1341-1349. 20. Hirakawa Y, Tanaka T, Nangaku M. Renal Hypoxia in CKD; Pathophysiology and Detecting Methods. Front Physiol. 2017; 8: 99. 21. Pallone TL, Silldorff EP, Turner MR. Intrarenal blood flow: microvascular anatomy and the regulation of medullary perfusion. Clin Exp Pharmacol Physiol. 1998; 25(6): 383-392.
| Chapter 1
| 18
22. Pallone TL, Morgenthaler TI, Deen WM. Analysis of microvascular water and solute exchanges in the renal medulla. The American journal of physiology. 1984; 247(2 Pt 2): F303-315.
23. Schlaich MP, Sobotka PA, Krum H, et al. Renal sympathetic-nerve ablation for uncontrolled hyperten-sion. N Engl J Med. 2009; 361(9): 932-934.
24. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009; 373(9671): 1275-1281.
25. Blantz RC, Deng A, Miracle CM, et al. Regulation of kidney function and metabolism: a question of supply and demand. Trans Am Clin Climatol Assoc. 2007; 118: 23-43.
26. Kiil F, Aukland K, Refsum HE. Renal sodium transport and oxygen consumption. The American journal
of physiology. 1961; 201: 511-516. 27. La Rovere MT, Pinna GD, Raczak G. Baroreflex sensitivity: measurement and clinical implications. Ann Noninvasive Electrocardiol. 2008; 13(2): 191-207. 28. La Rovere MT, Specchia G, Mortara A, et al. Baroreflex sensitivity, clinical correlates, and cardiovascu-lar mortality among patients with a first myocardial infarction. A prospective study. Circulation. 1988; 78(4): 816-824.
29. Osterziel KJ, Hanlein D, Willenbrock R, et al. Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure. Br Heart J. 1995; 73(6): 517-522. 30. Sleight P. The importance of the autonomic nervous system in health and disease. Aust N Z J Med. 1997; 27(4): 467-473. 31. La Rovere MT, Bigger JT, Jr., Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in predic-tion of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998; 351(9101): 478-484.
32. Brook RD, Julius S. Autonomic imbalance, hypertension, and cardiovascular risk. Am J Hypertens. 2000; 13(6 Pt 2): 112S-122S. 33. Palatini P. Sympathetic overactivity in hypertension: a risk factor for cardiovascular disease. Current hypertension reports. 2001; 3 Suppl 1: S3-9. 34. Grassi G, Dell’Oro R, Quarti-Trevano F, et al. Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia. 2005; 48(7): 1359-1365. 35. Thorp AA, Schlaich MP. Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome. J Diabetes Res. 2015; 2015: 341583.
36. Hausberg M, Grassi G. Mechanisms of sympathetic overactivity in patients with chronic renal failure: a role for chemoreflex activation? J Hypertens. 2007; 25(1): 47-49.
37. Hering D, Zdrojewski Z, Krol E, et al. Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure. J Hypertens. 2007; 25(1): 157-161. 38. Park J, Campese VM, Middlekauff HR. Exercise pressor reflex in humans with end-stage renal disease.
Am J Physiol Regul Integr Comp Physiol. 2008; 295(4): R1188-R1194.
39. Kones R. Oxygen therapy for acute myocardial infarction-then and now. A century of uncertainty. The
American journal of medicine. 2011; 124(11): 1000-1005.
40. Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. Circulation. 2015; 131(24): 2143-2150. 41. Ganz W, Donoso R, Marcus H, et al. Coronary hemodynamics and myocardial oxygen metabolism dur-ing oxygen breathing in patients with and without coronary artery disease. Circulation. 1972; 45(4): 763-768. 42. Thomson AJ, Webb DJ, Maxwell SR, et al. Oxygen therapy in acute medical care. BMJ. 2002; 324(7351): 1406-1407.
C
ha
pt
er
1
43. Pruijm M, Hofmann L, Maillard M, et al. Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men. Hypertension. 2010; 55(5): 1116-1122. 44. Rossi C, Sharma P, Pazahr S, et al. Blood oxygen level-dependent magnetic resonance imaging of the kidneys: influence of spatial resolution on the apparent R2* transverse relaxation rate of renal tissue. Invest Radiol. 2013; 48(9): 671-677. 45. Liss P, Cox EF, Eckerbom P, et al. Imaging of intrarenal haemodynamics and oxygen metabolism. ClinExp Pharmacol Physiol. 2013; 40(2): 158-167.
46. Pedersen M, Dissing TH, Morkenborg J, et al. Validation of quantitative BOLD MRI measurements in kidney: application to unilateral ureteral obstruction. Kidney Int. 2005; 67(6): 2305-2312. 47. Pruijm 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; 9(4): e95895. 48. Michaely HJ, Metzger L, Haneder S, et al. Renal BOLD-MRI does not reflect renal function in chronic kidney disease. Kidney Int. 2012; 81(7): 684-689. 49. Macia-Heras M, Del Castillo-Rodriguez N, Navarro Gonzales JF. The Renin-Angiotensin-Aldosterone System in Renal and Cardiovascular Disease and the Effects of its Pharmacological Blockade. Journal
of Diabetes & Metabolism. 2012; 3(1): 24.
50. Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007; 59(3): 251-287. 51. Schachinger H, Klarhofer M, Linder L, et al. Angiotensin II decreases the renal MRI blood oxygenation level-dependent signal. Hypertension. 2006; 47(6): 1062-1066. 52. Siddiqi L, Hoogduin H, Visser F, et al. Inhibition of the renin-angiotensin system affects kidney tis-sue oxygenation evaluated by magnetic resonance imaging in patients with chronic kidney disease.
Journal of clinical hypertension (Greenwich, Conn). 2014; 16(3): 214-218.
53. Vink EE, de Boer A, Hoogduin HJ, et al. Renal BOLD-MRI relates to kidney function and activity of the renin-angiotensin-aldosterone system in hypertensive patients. J Hypertens. 2015; 33(3): 597-604; discussion 601-592. 54. Stein A, Goldmeier S, Voltolini S, et al. Renal oxygen content is increased in healthy subjects after angiotensin-converting enzyme inhibition. Clinics. 2012; 67(7): 761-765. 55. Joyner MJ, Shepherd JT, Seals DR. Sustained increases in sympathetic outflow during prolonged lower body negative pressure in humans. J Appl Physiol. 1990; 68(3): 1004-1009.
56. Hirsch AT, Levenson DJ, Cutler SS, et al. Regional vascular responses to prolonged lower body negative pressure in normal subjects. Am J Physiol. 1989; 257(1 Pt 2): H219-H225.
57. Rowell LB, Seals DR. Sympathetic activity during graded central hypovolemia in hypoxemic humans.
Am J Physiol. 1990; 259(4 Pt 2): H1197-H1206.
58. Tidgren B, Hjemdahl P, Theodorsson E, et al. Renal responses to lower body negative pressure in humans. The American journal of physiology. 1990; 259(4 Pt 2): F573-579.
59. Gilbert CA, Bricker LA, Springfield WT, Jr., et al. Sodium and water excretion and renal hemodynamics during lower body negative pressure. J Appl Physiol. 1966; 21(6): 1699-1704.
60. Wurzner G, Chiolero A, Maillard M, et al. Renal and neurohormonal responses to increasing levels of lower body negative pressure in men. Kidney Int. 2001; 60(4): 1469-1476.
61. Koeners MP, Vink EE, Kuijper A, et al. Stabilization of hypoxia inducible factor-1alpha ameliorates acute renal neurogenic hypertension. J Hypertens. 2014; 32(3): 587-597.
62. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997; 77(1): 75-197.
63. O’Connor PM. Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol
| Chapter 1 | 20 64. Davy KP, Seals DR, Tanaka H. Augmented cardiopulmonary and integrative sympathetic baroreflexes but attenuated peripheral vasoconstriction with age. Hypertension. 1998; 32(2): 298-304. 65. Le Bihan D, Breton E, Lallemand D, et al. MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology. 1986; 161(2): 401-407. 66. Le Bihan D, Breton E, Lallemand D, et al. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology. 1988; 168(2): 497-505. 67. Muller MF, Prasad PV, Edelman RR. Can the IVIM model be used for renal perfusion imaging? Eur J Radiol. 1998; 26(3): 297-303. 68. Thoeny HC, De Keyzer F, Oyen RH, et al. Diffusion-weighted MR imaging of kidneys in healthy volun-teers and patients with parenchymal diseases: initial experience. Radiology. 2005; 235(3): 911-917. 69. Chandarana H, Lee VS, Hecht E, et al. Comparison of biexponential and monoexponential model of diffusion weighted imaging in evaluation of renal lesions: preliminary experience. Invest Radiol. 2011; 46(5): 285-291. 70. Sulkowska K, Palczewski P, Duda-Zysk A, et al. Diffusion-weighted MRI of kidneys in healthy volunteers and living kidney donors. Clin Radiol. 2015; 70(10): 1122-1127. 71. Eisenberger U, Thoeny HC, Binser T, et al. Evaluation of renal allograft function early after transplanta-tion with diffusion-weighted MR imaging. European radiology. 2010; 20(6): 1374-1383. 72. van Baalen S, Leemans A, Dik P, et al. Intravoxel incoherent motion modeling in the kidneys: Compari-son of mono-, bi-, and triexponential fit. Journal of magnetic resonance imaging : JMRI. 2016. § Cancer Research UK / Wikimedia Commons (2015, 8 December). “Diagram showing how the kidneys
work”. Retrieved from: https: //upload.wikimedia.org/wikipedia/commons/6/6f/ Diagram_show-ing_how_the_kidneys_work_CRUK_138.svg. Creative Commons licence: BY-SA 4.0
