Cardiorenal Syndrome
An Evolutionary Point of View
Sadayoshi Ito
I
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n modern societies, lifestyle-related diseases, such as
hypertension, diabetes mellitus, and obesity, are major
causes of cardiovascular disease (CVD) and renal failure. In
particular, chronic kidney disease (CKD), as defined by
reduced glomerular filtration rate (GFR; ⬍60 mL/min per
1.73 m2) and/or the presence of renal damage for ⬎3 months,
is a significant threat to public health. Recent epidemiological
studies have demonstrated that CKD is a significant risk for
cardiovascular events independent of classic risk factors, such
as hypertension, dyslipidemia, and diabetes mellitus.1 The
incidence and prevalence of CKD are increasing worldwide,
and CKD is a significant health problem associated with high
morbidity, mortality, and healthcare costs. One of the features
of lifestyle-related diseases is that an apparently minor insult
to the kidney, as manifested by microalbuminuria, is associated with a heightened incidence of CVD. Why? We may be
able to find an answer in the process of the evolution of life.2,3
It is plausible that the structures and functions of vital organs
and molecules essential for survival in the natural environment have now become villains that jeopardize our health in
a modern society. The representative examples may include
the renin-angiotensin-aldosterone system (RAAS) and the
circulatory systems that deliver blood supply to the sites
crucial for survival, such as the brain stem.
Cardiorenal syndrome is classified into 5 subtypes.4 This
review mainly discusses the relationship among the kidney,
heart, and brain in lifestyle-related diseases. However, an
insight into the fundamentals of structures and functions of
vital organs from an evolutionary point of view would help us
understand the pathophysiological interactions in the other
types of cardiorenal syndromes.
mesangium. The fact that the JGA appears first in amphibian
species in evolution suggests that the transition from aquatic
life to terrestrial life required this particular structure and its
functions.6 The primary functions of the JGA are the control
of renin release and the autoregulation of renal blood flow
and GFR. The macula densa, a plaque of specialized tubular
epithelial cells, is the sodium sensor of the body that controls
the rate of renin release and the tone of glomerular afferent
arteriole. The first direct evidence for the role of the macula
densa in the control of renin release and afferent arteriolar
tone was reported by Ito and colleagues.7–9
Figure 1 illustrates the anatomic relationships of the renal
vasculature and tubular segments. The major functions of the
cortex are the creation of a huge amount of glomerular filtrate
and reabsorption of most of the essential elements for life,
whereas the major function of medulla is urine concentration
and dilution. The kidney is one of the organs that receive
abundant blood supply. Renal blood flow amounts to as much
as 20% of cardiac output, ⬎90% of which is distributed to the
renal cortex. To maintain a high and stable GFR, efficient
mechanisms of autoregulation exist in the cortex so that renal
blood flow and GFR remain constant in the face of large
variations in systemic blood pressure (BP). On the other
hand, medullary blood flow is not well autoregulated, so that
an increase in systemic BP results in an increase in medullary
blood flow.10 This increase in medullary blood flow seems to
be an essential component of pressure natriuresis.
Teleological Significance of the Structure and
Function of the Kidney
The outer medulla is the anatomic site most susceptible to
ischemic injuries.11 As shown in Figure 1, blood flow to the
renal medulla is supplied by the descending vasa recta, which
emanate from the efferent arterioles of the juxtamedullary
glomeruli. In the outer medulla, particularly in the inner
stripe, descending vasa recta (containing arterial blood) and
ascending vasa recta (containing venous blood) run side by
side in opposite directions, forming a countercurrent circulation. Oxygen thereby diffuses from the descending to the
ascending vasa recta, reducing the oxygen content as blood
descends through the vasa recta vessels. In addition, oxygen
consumption is very high in the outer medulla because of the
Structure of the Mammalian Kidney
In all creatures, the milieu intérieur is kept constant, and this
stability is essential to various cellular functions and, therefore, maintenance of life.5 In mammals, the kidney is the
primary organ responsible for the maintenance of the milieu
intérieur of the body. The mammalian kidney has several
unique futures; for example, it has both long-loop and
short-loop nephrons and the juxtaglomerular apparatus
(JGA). The JGA is composed of glomerular afferent and
efferent arterioles, the macula densa, and extraglomerular
Received April 1, 2012; first decision April 16, 2012; revision accepted June 6, 2012.
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University School of Medicine, Sendai,
Miyagi, Japan.
Correspondence to Sadayoshi Ito, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan 980 – 8574. E-mail [email protected]
(Hypertension. 2012;60:589-595.)
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.111.188706
589
590
Hypertension
September 2012
Superficial
glomerulus
Cortex
Juxtamedullary
glomerulus
Outer
Medulla
Outer
stripe
Inner
stripe
Arcuate artery
mTALof short- loop
nephron
Collecting duct
Inner
Medulla
Figure 1. Anatomic structures of the renal vasculature and the tubular segments. The medullary thick
ascending limb (mTAL) of juxtamedullary nephron is
located in close vicinity to the vasa recta bundle.
The afferent arteriole of juxtamedullary nephron is
the first branch of the interlobular artery. Details are
described in the text.
Vasarecta
bundle
mTAL of juxtamedullary
(long -loop) nephron
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high levels of active ion transport in the medullary thick
ascending limbs of the loops of Henle (mTALs) and proximal
straight tubules, thereby reducing the oxygen content even
further in this region. In contrast, oxygen consumption is low
in the inner medulla because there is no active transport by
the thin loop of Henle, and, therefore, tissue oxygen tension
is well preserved.
Although the structure of the kidney looks complex, there
are certain principals in terms of the length of the loop of
Henle and the interrelationship between tubular segments and
vasculatures. The juxtamedullary nephron has a long loop,
and its efferent arteriole gives rise to the descending vasa
recta, whereas both the midcortical nephron and superficial
nephron have a short loop, and their efferent arterioles form
peritubular capillary networks. Some superficial nephrons
have even shorter loops that remain within the cortex. In
the medulla, the collecting duct is located at the midpoint
between the vascular bundles of the vasa recta. The
interbundle territory is organized with the long loops of the
juxtamedullary nephrons lying closest to the vascular
bundle. Shorter loops arising from superficial glomeruli
are more peripheral and, therefore, closer to the collecting
ducts. Because of these anatomic relationships, mTALs of
the superficial nephron are the tubular segments most
vulnerable to ischemic injuries, because their location is
far from the vascular bundle. Indeed, it has been reported
that the characteristic renal pathology of acute kidney
injuries is the necrosis of mTALs close to the collecting
duct.11
The above-mentioned structures enable the kidney to
maintain a high GFR and a high reabsorption rate, whereas
avoiding ischemic renal injuries even in the face of limited
salt intake and low systemic BP. When sodium intake is low
and systemic BP is reduced, the JGA increases renin release
and autoregulates glomerular hemodynamics. An increase in
renin release would raise the levels of circulating and intrarenal angiotensin II (Ang II). The autoregulation and preferen-
tial efferent (over afferent) arteriolar vasoconstrictor action of
Ang II would mitigate a decrease in GFR in individual
nephrons. In addition, there are heterogeneities in the vasoconstrictor actions of Ang II in the superficial and juxtamedullary afferent arterioles. By microperfusing the afferent
arteriole in vitro, we have shown that vasoconstriction induced by intraluminal Ang II is much stronger in the
superficial than in the juxtamedullary afferent arterioles, with
maximal constriction being 70% and 30%, respectively.12
Because of the strong constriction of the distal branches
(superficial afferent arterioles), intraluminal pressure in the
proximal segment of the interlobular artery would be increased. These changes in intrarenal hemodynamics combined with the weak constriction of juxtamedullary afferent
arterioles would decrease superficial single nephron GFR and
increase juxtamedullary single nephron GFR. Thus, the heterogeneity of Ang II action may explain the redistribution of
renal blood flow and GFR from superficial to juxtamedullary
cortex induced by sodium depletion or administration of Ang
II.13,14 Taken together, when Ang II is elevated, the total GFR
remains relatively constant, whereas the fraction of glomerular filtrate passing through the juxtamedullary nephrons
increases. On the one hand, this increase in filtered load of
sodium to long-loop nephrons would facilitate efficient recovery of filtered sodium. On the other hand, an increase
in tubular sodium load would increase oxygen demand in
the juxtamedullary nephrons. However, mTALs of these
nephrons are located in the vicinity of the vasa recta, and,
therefore, oxygen supply would be enough to avoid ischemic
injuries of this nephron segment. In terms of protection of
mTALs of superficial nephrons, the most vulnerable tubular
segment to ischemic injuries, the decreases in the single
nephron GFR combined with increased proximal tubular
absorption (by increased filtration fraction and Ang II level)
would greatly reduce the amount of sodium delivered to
mTALs. This would reduce oxygen demand and prevent
ischemic injuries of mTALs of the superficial nephrons.
Ito
Thus, a kidney is sophisticatedly designed structurally and
functionally so that a high GFR and electrolyte balances are
maintained even under a very low sodium intake and low
systemic BP while protecting the kidney itself from ischemic
injuries. When we look into the kidney from the teleological
point of view, we can understand the necessity of its complex
and well-organized structures and functions.
Albuminuria as a Cardiorenal Risk
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Epidemiological studies have established that reduced GFR
and increased urinary albumin excretion are related to heightened incidences of cardiovascular morbidity and mortality.1
Microalbuminuria is of particular interest, because it is a
significant risk factor not only in diabetic and hypertensive
subjects but also in the general population.1 Studies have now
shown that albuminuria even within the reference range is
associated with higher incidence and prevalence of CVD,1
and this risk increases in a continuous fashion with the degree
of albuminuria. It is of note that albuminuria is a predictor for
adverse cardiovascular events independent of the GFR, suggesting that albuminuria and reduced GFR have distinct
mechanisms as cardiovascular risks.
The mechanisms of the association between albuminuria
and CVD are still largely unknown and are a focus of
intensive research and debate. It has been suggested that
albuminuria not only reflects glomerular damage but also is a
sensitive indicator of generalized endothelial dysfunction and
capillary vasculopathy that leads to penetration of atherosclerotic lipoproteins into the arterial walls.15 Studies showed that
albuminuria was associated with endothelial dysfunction in
the systemic circulation,16 but not all studies support this
contention.17
Microalbuminuria results from glomerular injuries and/or
reduced tubular reabsorption of filtered albumin. It is unlikely
that all 2 million nephrons within the human kidney contribute equally to a miniscule amount of albumin leaking into
urine. It is more probable that some nephrons are damaged,
leaking a substantial amount of albumin, whereas the majority of others are not. Indeed, by using immunohistochemical
staining for albumin, Kralik et al18 reported that the kidney
from albuminuric type 2 diabetic subjects showed a heterogeneous pattern of staining, suggesting that albuminuria
originates only from a small fraction of nephrons. The
question is whether the nephron damage occurs randomly
among all of the nephrons or according to some principle. A
random phenomenon would be difficult to explain such a
close linkage between microalbuminuria and CVD, because
there is no logical necessity. However, if there is a principle
that causes nephron damage in certain subpopulations, and
if the same principle applies to some mechanisms of CVD,
then it would be able to explain the close linkage.
Strain Vessel Hypothesis
In hypertensive renal injury, considerable heterogeneities
exist among different nephron populations. Specifically,
tissue injury is most obvious in the juxtamedullary region
and outer medulla in spontaneously hypertensive rats19
Dahl salt-sensitive hypertensive rats,20 renovascular hypertension,21 and Ang II–induced hypertension.22 In addi-
Destiny of Evolution
591
tion, it has been shown that, in spontaneously hypertensive
rats, glomerular lesions first appear predominantly in the
juxtamedullary nephrons and then extend toward more
superficial nephrons.19 Such distinct localization of renal
injuries and mode of progression may be related to
anatomic and functional heterogeneities of different
nephron populations.
As shown in Figure 1, the juxtamedullary glomeruli are
located deep in the cortex, and their afferent arterioles arise
from either the initial segment of the interlobular artery or
directly from the arcuate artery. In more superficial nephrons,
their glomerular afferent arterioles branch off from the more
distal segments of the interlobular arteries. Because glomerular capillary pressure is normally maintained at ⬇50 mm Hg
by autoregulation in all nephrons,23 the pressure gradient
across the afferent arteriole would be greatest in the juxtamedullary nephron. In other words, the juxtamedullary
afferent arteriole is exposed to unusually high pressure for a
vessel of its size (⬇20 ␮m) and is destined to maintain strong
vascular tone to provide this large pressure gradient in a
short distance between the large arcuate artery and the
glomerulus. In contrast, in the superficial nephrons, a more
gradual pressure reduction occurs along the greater length
of vasculature, including the entire interlobular artery and
afferent arterioles. It is of note that the interlobular artery
also participates in renal autoregulation,24,25 and, therefore, the feeding pressure of superficial afferent arterioles
is substantially lower than that of juxtamedullary afferent
arterioles.24
There are many diseases and mechanisms proposed to
cause microalbuminuria. As discussed above, however, regardless of the pathogenesis of microalbuminuria, the anatomic sites that are injured initially or more severely are the
juxtamedullary afferent arterioles and glomeruli. It would be
reasonable to expect that, in the early stages of hypertension,
diabetes mellitus, or aging, renal injury occurs predominantly
in the juxtamedullary nephrons, whereas the majority of
other nephrons remain relatively intact. This would be
expected to result in only minimal increases in urinary
albumin excretion. Indeed, we observed that, in OtsukaLong-Evans-Tokushima-Fatty rats, podocyte injuries, as
measured by desmin staining, were evident only in the
juxtamedullary but not superficial glomeruli in an early
stage of developing albuminuria.26
From the hemodynamic point of view, the juxtamedullary
afferent arterioles are small and short vessels that are exposed
to a high and pulsatile pressure and destined to maintain
strong vascular tone to provide a large pressure gradient in a
short distance. We refer to these kinds of vessels as “strain
vessels.”2,3 Thus, microalbuminuria may be an early marker
of vascular damages of strain vessels within the body. Other
strain vessels exist most notably in the central nervous
system, where many perforating arteries arise directly from
large high-pressure arteries, such as anterior, middle, or
posterior cerebral arteries, and penetrate into the brain tissues
(Figure 2). As in the case of juxtamedullary afferent arterioles, these perforating arteries are exposed to a high pressure
and destined to maintain high vascular tone to provide large
pressure gradients from their parent arteries to brain tissue
592
Hypertension
September 2012
Pressure becoming lower
50 mmHg
Arteriolar damages
50 mmHg
Gl Hypertension
Arcuate artery
High pressure
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Strain vessels
・High pressure
・Pulsatile pressure
・High vascular tone
Figure 2. Strain vessels similar to juxtamedullary
afferent arteriole (left) within the body. Top right,
Perforating arteries in the central nervous system.
Bottom right, Coronary arteries. These are the
vessels that are exposed to very high pressure and
maintain a high vascular tone (a strain vessel).
Microalbuminuria may be an indicator of vascular
damage to these strain vessels.
Albumin leakage
capillaries. It is well known that the sites of hemorrhage or
infarction in the brain are frequently the areas of blood supply
governed by these perforating arteries.27 Thus, “strain vessels
injuries” may explain the link between vascular damage and
microalbuminuria in the kidney and stroke.
Central Hemodynamics as a Possible Link
Between Albuminuria and CVD
Unlike strain vessels in the kidney and central nervous
system, coronary arteries do not provide a pressure gradient.
However, they are also under high-pressure hemodynamic
conditions with a strong vascular tone, having the common
features of the strain vessel. It is well known that coronary
blood flow depends primarily on diastolic and not on systolic
BP. Coronary arteries arise directly from the aorta, and during
the systolic phase there is little coronary blood flow because
intramyocardial vessels are compressed because of myocardial contraction. This creates a unique situation that, during
the systolic phase, the entire epicardial segments of coronary
arteries, including small arteries just before their entering the
myocardium, are exposed to a very high pressure, because
there is little outflow. Studies have shown that coronary
arteries (particularly small-sized segments) exhibit myogenic
responses,28 so that when intraluminal pressure is elevated,
they would contract strongly to maintain vascular integrity. In
addition, the coronary blood flow is intermittent, and there
would be some reverse flow in coronary arteries during
myocardial contraction. Thus, the endothelium of coronary
arteries is exposed to huge variations of the shear stress, a
condition known to facilitate the formation of atherosclerotic
lesions.
Central BP measured at the aorta differs from BP measured
at the brachial artery.29 Because coronary arteries arise
directly from the aorta, the coronary circulation would be
greatly influenced by central hemodynamics. It is well known
that increased arterial stiffness accelerates pulse wave velocity and results in higher systolic and lower diastolic BP in the
central aorta. Such changes in central hemodynamics would
further aggravate turbulence of blood flow and variations of
shear stress imposed on the endothelium of the coronary
arteries. Likewise, central hemodynamics would greatly impact on strain vessels of the kidney and central nervous
system. Munakata et al30,31 have shown that pulse wave
velocity is associated with the degree of albuminuria in
general and hypertensive populations. In addition, Hashimoto
and Ito32 have shown recently that central pulse pressure is
closely related to changes in renal hemodynamics (resistive
index of renal segmental artery) and urinary albumin excretion rate. It has been reported that a high pulse wave velocity
and altered central hemodynamics are associated with high
event rates of CVD independent of BP measure at the upper
arm.33–35 Thus, central hemodynamics may be a common
basis for the associations among albuminuria, stroke, and
coronary arterial disease. Unlike other small vessels in
peripheral circulation where blood flow and pressure are
rather constant, the strain vessels are exposed to pulsatile
pressure and flow, and, therefore, stiffness of large arteries
would have a great impact on the burden imposed on strain
vessels.29
Albuminuria and Salt Sensitivity of BP
One of the features of microalbuminuria is the close association with salt sensitivity of BP,36–38 and this association is
observed even in normotensive subjects.39 Salt-sensitive hypertension is characterized by glomerular hypertension, microalbuminuria, and a higher mortality and morbidity of
cardiovascular events.38,39
There are many mechanisms involved in the salt sensitivity
of BP, and one such mechanism may be impaired pressure
natriuresis. When salt is ingested with meals, various neurohormonal changes, such as inhibition of the RAAS and
enhanced production of prostaglandin and NO, occur and
thereby increase GFR and reduce tubular sodium reabsorption. It has been shown that, in humans, ingestion of a high
protein meal induces a substantial (⬇40%) increase in corti-
Ito
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cal blood flow.40 Although there is no report on the measurement of medullary blood flow in humans, animal experiments
have shown that an acute infusion of saline or amino acids
increases medullary blood flow41,42 and that an increase in
medullary blood flow promotes natriuresis. The postmeal
natriuretic response seems to be accounted for by an early
(0 –90 minutes) increase in glomerular filtered load of
sodium and a late (90 –180 minutes) reduction in tubular
sodium reabsorption.43 These acute changes in renal function play an important role in achieving daily sodium
balance, and when these changes fail to accomplish a
complete sodium balance, extracellular volume increases,
resulting in an elevation in BP. This elevation in BP then
increases sodium excretion (pressure natriuresis), and one
of the mechanisms of pressure natriuresis is the increase in
medullary blood flow.
According to our strain vessel hypothesis, microalbuminuria indicates the existence of damage in juxtamedullary
afferent arterioles and glomeruli and, therefore, impairments
of the downstream medullary circulation. Because the medullary circulation plays a crucial role in the mechanisms of
pressure natriuresis,10 microalbuminuria may be related to
impaired pressure natriuresis and, therefore, salt sensitivity of
BP. In addition, in the early stages of juxtamedullary glomerular injuries, there may be functional alterations in vasa recta.
Namely, glomerular hypertension/hyperfiltration in the juxtamedullary glomeruli may cause constriction of descending
vasa recta and thereby functionally impair renal medullary
circulation. It is of note that mTALs of the juxtamedullary
nephron are located close to the vasa recta that supply blood
to the medulla. Mori and colleagues44,45 have demonstrated
the presence of tubulovascular cross-talk in which NO or
superoxide produced by the mTALs can diffuse into pericytes
of descending vasa recta. By microperfusing mTAL segments
in vitro, Abe et al46 demonstrated that an increase in sodium
chloride concentration of the tubular perfusate stimulates
superoxide anion production and decreases NO. Thus, hyperfiltration in juxtamedullary nephrons would increase sodium
delivery to their own mTAL and stimulate superoxide production, which, in turn, may cause vasoconstriction of the
descending vasa recta. Thus, our strain vessel hypothesis may
explain close interrelationships among microalbuminuria, salt
sensitivity of BP, and cerebrocardiovascular mortality and
morbidity. It should be noted, however, that other factors,
such as the RAAS and insulin sensitivity, also play a role in
salt sensitivity of BP.
CKD Components as Cardiorenal Risks
As mentioned above, in such diseases as hypertension,
diabetes mellitus, and obesity, vascular injuries occur first in
the strain vessels. The renal manifestations of the injuries are
microalbuminuria and salt sensitivity of BP, and both would
be significant risk factors for CVD because they may indicate
strain vessel injuries in other vital organs. As endothelial and
vascular damage become advanced, more and more glomeruli
are injured, resulting in a substantial amount of albuminuria
and reduced GFR. In addition, proteinuria induces tubulointerstitial damage within the kidney, thereby contributing
to a further decline in GFR. Therefore, overt albuminuria
Destiny of Evolution
593
is a strong risk factor for both renal and cardiovascular
events in subjects with hypertension, diabetes mellitus,
and/or obesity.
In contrast to lifestyle-related diseases, overt albuminuria
does not seem to be a significant risk factor for CVD in
primary glomerular diseases. Urine abnormality is the first
sign of primary glomerular disease, and its manifestation is
often proteinuria (macroalbuminuria) rather than microalbuminuria. The degree of urine abnormalities reflects the degree
of glomerular injury but not strain vessel injuries. Therefore,
albuminuria alone may not be a risk factor for CVD because
strain vessels are not the primary sites of injuries.
Once renal function is reduced regardless of the original
cause, numerous nonclassic risk factors come in to play for
further aggravation of renal dysfunction and endothelial and
vascular injuries. They include oxidative stress, inflammation, bone-mineral disorder, anemia, and so forth. Both
classic and nonclassic risk factors induce renal damage, and
renal dysfunction further aggravates classic risk factors, as
well as nonclassic risk factors, thereby forming a vicious
cycle. Both classic and nonclassic risk factors are powerful
accelerators of atherosclerosis. It has been shown that even
moderate renal dysfunction is associated with enhanced
oxidative stress and inflammation, which, in turn, accelerate
atherosclerosis in the general circulation.
An Evolutionary Point of View
and Perspectives
Why do we have such vulnerable structures as strain vessels
or the RAAS that may cause organ damage? From the
evolutionary point of view, we speculate that unique structures such as strain vessels in vital organs, as well as
neurohormonal systems such as the RAAS, would have been
essential for creatures on the land to survive under their
natural environments. All creatures, in their natural environments, were constantly facing the danger of circulatory
collapse and starvation. Given the generally difficult access to
salt and a high risk of wound injuries, hypotension and
hypoperfusion of vital organs were the principal challenges
with which they had to cope. For this purpose, the complex
and well-organized renal structures, sophisticated integration
of various renal functions, and the potent vasoconstrictor and
sodium-retaining actions of RAAS were all indispensable. In
addition, to maintain the perfusion of the vital tissues, such as
brain stem, it was necessary to develop circulatory systems in
which vessels are branched off directly from the large arteries
and deliver blood to the tissue. Without sufficient evolutionary time to adapt to the modern diets of the rapidly developed
industrialized societies, the organisms were not designed to
cope with high salt intake, hypertension, and obesity, as
reviewed elsewhere.47–50 Taken together, the close link between CKD and CVD may be viewed as an inevitable
consequence destined by evolution. In other words, although
we human beings enjoy the benefits of many developments
after the industrial revolution, we have to keep in mind that
our fate is still governed by the natural laws of evolution.
Thus, perspectives from an evolutionary point of view may
explain why hypertension and diabetes mellitus, unforeseen
594
Hypertension
September 2012
in the concept of evolution, preferentially affect vital organs
such as the brain, heart, and kidney.
Acknowledgments
I thank S Muryoi for her expert secretarial assistance.
Sources of Funding
This work was supported by the Global Center of Excellence
Program research grant; Grant-in-Aid (No 21390259 and No
22659164) for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan; and the research
grant from the Ministry of Health, Labor, and Welfare of Japan
(H22-SeiShu-005 and H21-renal disease-001).
Disclosures
The author received lecture fees and grant supports from Boehringer
Ingelheim; Daiichi-Sankyo Co LTD, MSD; Novartis Pharma KK;
Astellas Pharma Inc; Shionogi & Co LTD; and Takeda Pharmaceutical Company Limited.
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References
1. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de
Jong PE, Coresh J, Gansevoort RT, for the Chronic Kidney Disease
Prognosis Consortium. Association of estimated glomerular filtration rate
and albuminuria with all-cause and cardiovascular mortality in general
population cohorts: a collaborative meta-analysis. Lancet. 2010;375:
2073–2081.
2. Ito S, Nagasawa T, Abe M, Mori T. Strain vessel hypothesis: a viewpoint
for linkage of albuminuria and cerebro-cardiovascular risk. Hypertens
Res. 2009;32:115–121.
3. Ito S. Cardiorenal connection in chronic kidney disease. Clin Exp
Nephrol. 2012;16:8–16.
4. Ronco C, Cozzolino M. Mineral metabolism abnormalities and vitamin D
receptor activation in cardiorenal syndromes. Heart Fail Rev. 2012;17:
211–220.
5. Gross CG. Claude Bernard and the constancy of the internal environment.
Neuroscientist. 1998;4:380–385.
6. Wilson JX. The renin-angiotensin system in nonmammalian vertebrates.
Endocr Rev. 1984;5:45–61.
7. Ito S, Carretero OA. Role of the macula densa in renin release. Hypertension.
1985;7:I49–54.
8. Ito S, Carretero OA. An in vitro approach to the study of macula
densa-mediated glomerular hemodynamics. Kidney Int. 1990;38:
1206–1210.
9. Ito S, Ren Y. Evidence for the role of nitric oxide in macula densa control
of glomerular hemodynamics. J Clin Invest. 1993;92:1093–1098.
10. Cowley AW Jr. Long-term control of arterial blood pressure. Physiol Rev.
1992;72:231–300.
11. Goldfarb M, Abassi Z, Rosen S, Shina A, Brezis M, Heyman SN.
Compensated heart failure predisposes to outer medullary tubular injury:
studies in rats. Kidney Int. 2001;60:607–613.
12. Ito S, Amin J, Ren Y, Arima S, Abe K, Carretero OA. Heterogeneity
of angiotensin action in renal circulation. Kidney Int. 1997;63:
S128–S131.
13. Gross V, Kurth TM, Skelton MM, Mattson DL, Cowley AW Jr. Effects
of daily sodium intake and ANG II on cortical and medullary renal blood
flow in conscious rats. Am J Physiol. 1998; 274;R1317–R1323.
14. Treeck B, Roald AB, Tenstad O, Aukland K. Effect of exogenous and
endogenous angiotensin II on intrarenal distribution of glomerular filtration rate in rats. J Physiol. 2002;541:1049–1057.
15. Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol.
2006;17:2106–2111.
16. Malik AR, Sultan S, Turner ST, Kullo IJ. Urinary albumin excretion
is associated with impaired flow- and nitroglycerin-mediated brachial
artery dilatation in hypertensive adults. J Hum Hypertens. 2007;21:
231–238.
17. Diercks GF, Stroes ES, van Boven AJ, van Roon AM, Hillege HL, de Jong
PE, Smit AJ, Gans RO, Crijns HJ, Rabelink TJ, van Gilst WH. Urinary
albumin excretion is related to cardiovascular risk indicators, not to flowmediated vasodilation, in apparently healthy subjects. Atherosclerosis. 2002;
163:121–126.
18. Kralik PM, Long Y, Song Y, Yang L, Wei H, Coventry S, Zheng S,
Epstein PN. Diabetic albuminuria is due to a small fraction of nephrons
distinguished by albumin-stained tubules and glomerula adhesions. Am J
Pathol. 2009;175:500–509.
19. Iversen BM, Amann K, Kvam FI, Wang X, Ofstad J. Increased glomerular capillary pressure and size mediate glomerulosclerosis in SHR
juxtamedullary cortex. Am J Physiol. 1998;274:F365–F373.
20. Johnson RJ, Gordon KL, Giachelli C, Kurth T, Skelton MM, Cowley AW
Jr. Tubulointerstitial injury and loss of nitric oxide synthases parallel the
development of hypertension in the Dahl-SS rat. J Hypertens. 2000;18:
1497–1505.
21. Eng E, Veniant M, Floege J, Fingerle J, Alpers CE, Menard J, Clozel JP,
Johnson RJ. Renal proliferative and phenotypic changes in rats with
two-kidney, one-clip Goldblatt hypertension. Am J Hypertens. 1994;7:
177–185.
22. Mori T, Cowley AW Jr. Role of pressure in angiotensin II-induced
renal injury: chronic servo-control of renal perfusion pressure in rats.
Hypertension. 2004;43:752–759.
23. Ericson AC, Sjöquist M, Ulfendahl HR. Heterogeneity in regulation of
glomerular function. Acta Physiol Scand. 1982;114:203–209.
24. Heyeraas KJ, Aukland K. Interlobular arterial resistance: influence of
renal arterial pressure and angiotensin II. Kidney Int. 1987;31:1291–1298.
25. Takenaka T, Suzuki H, Okada H, Hayashi K, Ozawa Y, Saruta T.
Biophysical signals underlying myogenic responses in rat interlobular
artery. Hypertension. 1998;32:1060–1065.
26. Sofue T, Kiyomoto H, Kobori H, Urushihara M, Nishijima Y, Kaifu K,
Hara T, Matsumoto S, Ichimura A, Ohsaki H, Hitomi H, Kawachi H,
Hayden MR, Whaley-Connell A, Sowers JR, Ito S, Kohno M, Nishiyama
A. Early treatment with olmesartan prevents juxtamedullary glomerular
podocyte injury and the onset of microalbuminuria in type 2 diabetic rats.
Am J Hypertens. 2012;25:604–611.
27. Greenberg SM. Small vessel, big problem. N Engl J Med. 2006;354:
1451–1453.
28. Cornelissen AJ, Dankelman J, VanBavel E, Stassen HG, Spaan JA.
Myogenic reactivity and resistance distribution in the coronary arterial
tree: a model study. Am J Physiol Heart Circ Physiol. 2000;278:
H1490–H1499.
29. O’Rourke MF, Safar ME. Relationship between aortic stiffening and
microvascular disease in brain and kidney: cause and logic of therapy.
Hypertension. 2005;46:200–204.
30. Munakata M, Miura Y, Yoshinaga K, for the J-TOPP study group. Higher
brachial-ankle pulse wave velocity as an independent risk factor for future
microalbuminuria in patients with essential hypertension: the J-TOPP
Study. J Hypertens. 2009;27:1466–1471.
31. Munakata M, Nunokawa T, Yoshinaga K, Toyota T, for the J-TOPP
Study Group. Brachial-ankle pulse wave velocity is an independent risk
factor for microalbuminuria in patients with essential hypertension: a
Japanese trial on the prognostic implication of pulse wave velocity
(J-TOPP). Hypertens Res. 2006;29:515–521.
32. Hashimoto J, Ito S. Pulse pressure amplification, arterial stiffness, and
peripheral wave reflection determine pulsatile flow waveform of the
femoral artery. Hypertension. 2010;56:926–933.
33. Huan Y, Townsend R. Is there a role for measuring central aortic
pressure? Curr Cardiol Rep. 2011;13:502–506.
34. Milan A, Tosello F, Fabbri A, Vairo A, Leone D, Chiarlo M, Covella M,
Veglio F. Arterial stiffness: from physiology to clinical implications.
High Blood Press Cardiovasc Prev. 2011;18:1–12.
35. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, Umans
JG, Howard BV. Central pressure more strongly relates to vascular
disease and outcome than does brachial pressure: the Strong Heart Study.
Hypertension. 2007;50:197–203.
36. Cubeddu LX, Hoffmann IS, Aponte LM, Nuñez-Bogesits R, MedinaSuniaga H, Roa M, Garcia RS. Role of salt sensitivity, blood pressure,
and hyperinsulinemia in determining high upper normal levels of urinary
albumin excretion in a healthy adult population. Am J Hypertens. 2003;
16:343–349.
37. Nesović M, Stojanović M, Nesović MM, Cirić J, Zarković M. Microalbuminuria is associated with salt sensitivity in hypertensive patients. J Hum
Hypertens. 1996;10:573–576.
38. Campese VM. Salt sensitivity in hypertension: renal and cardiovascular
implications. Hypertension. 1994;23:531–550.
39. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans.
Hypertension. 2001;37:429–432.
Ito
40. Kalantarinia K, Belcik JT, Patrie JT, Wei K. Real-time measurement of
renal blood flow in healthy subjects using contrast-enhanced ultrasound.
Am J Physiol Renal Physiol. 2009;297:F1129–F1134.
41. Miyata N, Zou AP, Mattson DL, Cowley AW Jr. Renal medullary
interstitial infusion of L-arginine prevents hypertension in Dahl saltsensitive rats. Am J Physiol. 1998;275:R1667–R1673.
42. Li N, Chen L, Yi F, Xia M, Li PL. Salt-sensitive hypertension induced by
decoy of transcription factor hypoxia-inducible factor-1␣ in the renal
medulla. Circ Res. 2008;102:1101–1108.
43. Cirillo M, Anastasio P, Spitali L, Santoro D, De Santo NG. Effects of a
meat meal on renal sodium handling and sodium balance. Miner Electrolyte Metab. 1998;24:279–284.
44. Mori T, Cowley AW Jr, Ito S. Molecular mechanisms and therapeutic
strategies of chronic renal injury: physiological role of angiotensin
II-induced oxidative stress in renal medulla. J Pharmacol Sci. 2006;
100:2–8.
Destiny of Evolution
595
45. Mori T, Cowley AW. Angiotensin II-NAD(P)H oxidase-stimulated
superoxide modifies tubulovascular nitric oxide cross-talk in renal outer
medulla. Hypertension. 2003;42:588–593.
46. Abe M, O’Connor P, Kaldunski M, Liang M, Roman RJ, Cowley AW
Jr. Effect of sodium delivery on superoxide and nitric oxide in the
medullary thick ascending limb. Am J Physiol Renal Physiol. 2006;
291:F350–F357.
47. Young JH. Evolution of blood pressure regulation in humans. Curr
Hypertens Rep. 2007;9:13–18.
48. Kurokawa K. Kidney, salt, and hypertension: how and why. Kidney Int.
Suppl. 1996;55:S46–S51.
49. Tobian L. Protecting arteries against hypertensive injury. Clin Exp
Hypertens. 1992;14:35–43.
50. Lee PY, Yun AJ, Bazar KA. Acute coronary syndromes and heart failure
may reflect maladaptations of trauma physiology that was shaped during
pre-modern evolution. Med Hypotheses. 2004;62:861–867.
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Cardiorenal Syndrome: An Evolutionary Point of View
Sadayoshi Ito
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Hypertension. 2012;60:589-595; originally published online July 2, 2012;
doi: 10.1161/HYPERTENSIONAHA.111.188706
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