.-Ischemic Renal Injury_REVISARLO.pdf

Ischemic Renal Injury: Can Renal Anatomy and
Associated Vascular Congestion Explain Why the
Medulla and Not the Cortex Is Where the Trouble
Starts?
Sarah C. Ray, BSc * June Mason, MD, PhD †,‡
and Paul M. O’Connor, PhD*
Summary: The kidneys receive approximately 20% of cardiac output and have a low fractional oxygen extraction.
Quite paradoxically, however, the kidneys are highly susceptible to ischemic injury (injury associated with inade-
quate blood supply), which is most evident in the renal medulla. The predominant proposal to explain this suscepti-
bility has been a mismatch between oxygen supply and metabolic demand. It has been proposed that unlike the
well-perfused renal cortex, the renal medulla normally operates just above the threshold for hypoxia and that further
reductions in renal perfusion cause hypoxic injury in this metabolically active region. An alternative proposal is that
the true cause of ischemic injury is not a simple mismatch between medullary metabolic demand and oxygen sup-
ply, but rather the susceptibility of the outer medulla to vascular congestion. The capillary plexus of the renal outer
medullary region is especially prone to vascular congestion during periods of ischemia. It is the failure to restore the
circulation to the outer medulla that mediates complete and prolonged ischemia to much of this region, leading to
injury and tubular cell death. We suggest that greater emphasis on developing clinically useful methods to help pre-
vent or reverse the congestion of the renal medullary vasculature may provide a means to reduce the incidence and
cost of acute kidney injury.
Semin Nephrol 39:520−529 Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Red blood cell, kidney, vasa recta, pericyte, hypoxia, oxygen
A
cute kidney injury (AKI), or a sudden reduction
in renal function, can have many causes, but
ischemic injury caused by reduced renal blood
flow is by far the most common.1
Observations made in
late-stage renal failure initially led to the term acute
tubular necrosis because extensive cortical necrosis was
seen as the defining characteristic. Later findings in
established kidney failure led to the term vasomotor
nephropathy because vasoconstriction was thought to
explain reduced renal blood flow.2
Later, the terms acute
renal failure and then acute kidney injury were intro-
duced to describe the condition, rather than its pathol-
ogy. The variety of terms, reflecting changing views of
the predominant pathology, often have described find-
ings made in advanced renal failure, when later events
may obscure the early events that started the process.
AKI is a major clinical problem that leads to increased
hospitalization time, increased hospital costs, increased
risk of long-term renal and cardiovascular complications,
and an increased mortality rate.3
The implementation of
standardized diagnostic criteria for AKI has shown that
the prevalence of AKI continues to increase, now affect-
ing one in five hospitalized adults worldwide.3,4
Overall,
the mortality rate for AKI is approximately 25%. How-
ever, the mortality rate exceeds 50% with increasing
severity of injury, dialysis-requiring AKI, and critical
care AKI patients.4,5
Furthermore, it is estimated that
approximately 2 million people in developed countries
die each year from complications associated with AKI.6,7
The frequency of the problem and its huge health eco-
nomic impact make it important to try to understand how
the most common form of AKI, which is caused by
ischemia (a reduction or stoppage of renal blood flow),
starts the chain of events that lead to persisting renal fail-
ure. Animal models have provided new evidence about
the nature and location within the kidney of the early
events that accompany renal ischemia. If the same events
occur in the clinical setting of ischemic AKI, this may
permit the development of preventative measures or
early treatments to reduce the occurrence of the sus-
tained renal damage and premature death.
In this article we focus on two unresolved but interre-
lated aspects of ischemic AKI. First, why is the kidney
so susceptible to ischemic damage? This seems to be
paradoxic in an organ whose blood flow far exceeds its
metabolic needs. Second, why are some regions of the
kidney particularly sensitive to ischemia in the early
stages of ischemic AKI? Most evidence indicates that
the renal medulla is affected much more than the renal
cortex. We then consider two theories to explain how
ischemic AKI might be initiated and the consequences
this may have for future research and treatment.
*Department of Physiology, Medical College of Georgia, Augusta
University, Augusta, Georgia
yPhysiology Institute, Ludwig-Maximilians University of Munich,
Munich, Germany
zMedical Writing, Novartis Pharmaceuticals, Basel, Switzerland
Financial support: NIH awards: PO1HL134604 and DK099548.
Conflict of interest statement: none.
Address reprint requests to Sarah C. Ray, BSc, Department of Physiol-
ogy, Medical College of Georgia, Augusta University, CB2200, 1459
Laney Walker Blvd, Augusta, GA 30912. E-mail: sray@augusta.edu
0270-9295/ - see front matter
© 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.semnephrol.2019.10.002
520 Seminars in Nephrology, Vol 39, No 6, November 2019, pp 520−529
Descargado para luis eduardo mendoza goez (lmendozag@hotmail.com) en University of Cartagena de ClinicalKey.es por Elsevier en agosto 22, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.

THE RENAL ISCHEMIC PARADOX
The kidneys, which receive approximately 20% of car-
diac output although accounting for less than 1% of total
body weight, are unusually susceptible to ischemic
injury. Under normal physiologic conditions renal blood
flow provides an ample supply of oxygen to the kidney,
which appears to exceed its metabolic requirements.
This is evident in renal oxygen extraction, which is low
(»10%-15%)8
compared with most metabolically active
tissues, which, similar to the heart, extract approximately
40% of the oxygen delivered8
and the relatively high tis-
sue PO2 of most of the renal parenchyma.9-11
Why then,
when the kidneys are so well perfused, are they so sus-
ceptible to ischemic injury? This paradoxic situation can
be referred to as the renal ischemia paradox.
To understand the situation, it is useful to review
some key aspects of renal anatomy, hemodynamics, and
tubular metabolic requirements. The renal cortex
receives 100% of renal blood flow that comes from all
glomeruli and supplies oxygen to most of the proximal
tubules. The renal medulla receives only 5% to 10% of
that blood flow, supplied by the juxtamedullary glomer-
uli, yet provides oxygen to much of the proximal straight
tubule (PST) and the medullary portion of the thick
ascending limb (mTAL) (Fig. 1). The tubular segments
in the cortex and the PST and the mTAL in the outer
medulla all are heavily involved in tubular transport,
which is dependent on oxidative metabolism. Tubular
segments in the inner medulla, in contrast, perform less
tubular transport and can derive their energy from anaer-
obic metabolism.
THE REGIONS OF THE KIDNEY MOST SENSITIVE
TO ISCHEMIC DAMAGE
Our understanding of the pathophysiology of ischemic
kidney injury has increased greatly over the past several
decades, showing that ischemic AKI is multifactorial
and includes tubular injury, vascular dysfunction, and
inflammation.12-15
It also has become clear that the
renal cortex is not the region predominantly affected by
tubular injury from ischemic damage1,12
and that
Figure 1. Schematics of the architecture of the renal vasculature. Left: Schematic arrangement of the arterial and venous
vasculature in the renal cortex and medulla.74
Right: Schematic diagram of the arterial and capillary blood supply (left),
the venous drainage (middle), and the tubular segments (right) in the cortex (C), outer stripes (OS), and inner stripes (IS)
of the outer medulla and the inner medulla (IM).64
Note the dense, highly branched capillary plexus in the inner stripe of
the outer medulla that lies between the vascular bundles of vasa recta capillaries. Abbreviation: A, artery; AVR, ascending
vasa recta; DVR, descending vasa recta; V, vein. Reproduced with permission from Kriz64
and Molema and Aird.74
Ischemic renal injury 521

vasoconstriction in the renal cortex is not the only
mechanism that suppresses renal function.16
Thus,
newer explanations are required that consider events
occurring in other regions of the kidney.
Tubular injury in the outer medulla, specifically in the
PST and mTAL segments, is common in both humans15
and in animal models12
of ischemic AKI. The PST and
mTAL both require high oxygen delivery to sustain the
oxidative adenosine triphosphate (ATP) production
needed for the tubular transport of sodium and chloride.
The continuation of tubular transport under ischemic
conditions likely leads to cell death via apoptosis or
necrosis.17
Studies using animal models of ischemic AKI have
provided evidence that both the PST and mTAL are
functionally impaired. Injured tubules show reduced lev-
els of tubular reabsorption and secretion as the Na+
K+
-
ATPase and the Na+
H+
exchanger are down-regulated.17
Loss of proximal tubule brush border and cell polarity
accompany further reductions of tubular transport in
ischemic injury. Although portions of the PST and TAL
are present in the renal cortex, the initial tubular injury
observed in ischemic AKI is much less evident in the
cortex and quite prominent in the renal medulla, where
extensive tubular necrosis is found.18-20
Accompanying the damage of the tubular segments
involved in oxidative metabolism in the outer medulla is a
prominent hyperemia of this region of the kidney. Further
investigation, however, showed a compact mass of aggre-
gated erythrocytes found mostly in the dense inner stripe
capillary plexus of the outer medulla (Fig. 2). This vascu-
lar congestion is a hallmark of ischemic AKI injury in
both experimental models21-24
and in patient biopsy speci-
mens and specimens obtained at autopsy.25-27
Its presence
suggests that it is the circulation in this region that is espe-
cially poor after ischemia.
THEORIES TO EXPLAIN THE RENAL ISCHEMIA
PARADOX
There are currently two main theories to explain the renal
ischemia paradox. The first theory originally was proposed
by Brezis et al28
and is based on the concept of a mismatch
between oxygen supply and metabolic demand. They pro-
posed that the high metabolic demand (high transport) of
the tubular cells in the outer medulla is an evolutionary
consequence of the ability to concentrate urine. Under
ischemic conditions, oxygen tension is low and continued
tubular transport is the cause of ischemic injury in the
tubular segments of the outer medulla. The second theory
was based on observations made in experimental models.
They proposed that because the outer medullary capillary
network is highly susceptible to vascular obstruction dur-
ing periods of reduced perfusion.21,22,29,30
Congestion of
the microvasculature then prevents reperfusion after the
initial ischemic event has passed and prolongs the period
of ischemia to this region.
Renal Oxygen/Metabolic Mismatch: Pros and
Contra
The theory
The dominant proposal to explain the renal ischemia para-
dox was first proposed by Brezis et al.28
It has long been
established that medullary blood flow accounts for only
5% to 10% of the total renal blood flow. The oxygen ten-
sion in the medullary tissue is significantly lower than in
arterial blood,9
and is only approximately 10 to 30 mm Hg
in the outer and inner medullas of rat11
and dog10
kidneys.
Cytochrome aa3 shows a 20% to 40% reduction in the
medulla (indicating mitochondrial anoxia),31,32
which nor-
malizes when tubular transport in the medulla is reduced
by the loop diuretic furosemide.32
These data led Brezis et
al28
to propose that “within the outer medulla, the medul-
lary thick ascending limb, which normally operates on the
verge of anoxia becomes a prime target for ischemic
injury” because of the delicate balance of regulating oxy-
gen supply and demand in this region. They suggested that
decreasing renal perfusion further causes hypoxic damage
in this at-risk medullary region.28
The pros of the theory are that it explains why the
medullary portions of the tubules are predominantly
affected by ischemia. The cons are that this region is rel-
atively well protected from hypoxia during periods of
(incomplete) ischemia and that there is little in vivo evi-
dence that the moderate levels of hypoxia that may result
will promote significant renal injury. In addition, this
theory has not led to any successful clinical interventions
that improve renal function or patient mortality.
Figure 2. Prominent vascular congestion (red blood cells sludging,
medullary hyperemia) in a rat kidney 24 hours after 45 minutes of
warm bilateral ischemia reperfusion (clamping). Note the pale cortex
and the highly congested (dark red) outer medullary region with
trapped red blood cells.
522 S.C. Ray, J. Mason, and P.M. O’Connor

Experimental ﬁndings
The assumption underlying the theory of Brezis et al,28
that there is a mismatch between oxygen supply and met-
abolic demand, is that the mTAL of the outer medulla is
“normally operating on the verge of anoxia” and that
decreasing renal oxygen delivery further would cause
hypoxic damage. Thus, it is relevant to examine whether
oxygen tension or tissue perfusion are critically low
under normal circumstances and in kidneys subjected
to decreased perfusion (ischemia) or oxygen delivery
(hypoxemia).
Observations under different conditions and in sev-
eral animal models have shown oxygen tension in the
renal medulla to be similar to that in the midcortex.33-35
These studies showed oxygen tension to be significantly
higher than the approximately 10 mm Hg28
reported in
the renal papilla of the inner medulla, which is affected
little by ischemia. Importantly, although blood flow to
the medulla is low relative to the cortex (5%-10%), this
level of perfusion and PO2 is similar to that of other
metabolically active tissues.8,36
Thus, rather than con-
sidering the perfusion and oxygen tension of the
medulla to be critically low, the perfusion and oxygen
tension of the outer cortex should be considered to be
exceptionally high.
Other observations also were not consistent with a
mismatch between oxygen supply and metabolic
demand. If the renal medulla really operates at near-
hypoxic conditions, it should be especially susceptible
to injury from systemic hypoxia. However, there is little
evidence that hypoxia alone causes a renal functional
decrease or significant injury.37,38
Gotshall et al39
showed that systemic hypoxia in dogs does not lead to
a reduction in renal function, a decrease in urine output,
or an increase in fractional sodium excretion that would
indicate impaired tubular reabsorption. Furthermore, in
experiments on rats, Yeh et al37
found that after
15 hours of hypobaric hypoxia (380 torr), renal function
(blood urea nitrogen/creatinine) was similar between
hypoxic and control animals but was subsequently
impaired 24 hours after 45 minutes of clamp ischemia.
Thus, at least in experimental models, the kidney is
very resistant to prolonged periods of arterial hypoxia.
Instead, periods of completely reduced blood flow
appear to be required to achieve any significant degree
of functional impairment.
Significant renal tissue hypoxia may not occur even
during periods of reduced renal perfusion that result in
ischemic AKI. This is because the reduced blood flow
also causes filtration, tubular reabsorption, and oxygen
use to be reduced similarly (Fig. 3).40-44
The reduced
level of work at reduced levels of perfusion is seen by
the relatively constant level of oxygen extraction by the
kidney at different levels of renal blood flow.45
Clinical observations
Pharmaceutical interventions that could support the con-
cept of a mismatch between oxygen supply and metabolic
need have shown little promise in the prevention or treat-
ment of ischemic AKI. Clinical trials have examined vas-
odilators to increase blood flow and oxygen delivery and
diuretics to decrease tubular transport and reduce oxygen
consumption. Vasodilators, such as theophylline,46,47
uro-
dilatin,48
fenoldopam,49
and rosuvastatin,50
and osmotic
diuretics such as mannitol,51
did not show improvements
in renal function or mortality rate in patients with AKI.
The use of the loop diuretic furosemide, which should
indicate the role of a mismatch between oxygen supply
and metabolic demands for transport in the medulla, also
has not been able to prevent or treat AKI. Loop diuretics
specifically inhibit the Na-K-Cl co-transporter in the
TAL and macula densa, which accounts for much of the
oxygen demand in the outer medulla, as indicated by a
significant increase in medullary oxygen tension in ani-
mal models52
and humans53
given furosemide. Therefore,
it has been proposed that furosemide, by reducing oxygen
consumption in the outer medulla,54
should protect the
kidney from ischemic damage during periods of hypoper-
fusion. By inhibiting tubule−glomerular feedback and
thereby promoting tubular flow, furosemide also may pre-
vent tubular obstruction after tubular cell death and sluff-
ing of cells into the tubular lumen.55,56
Clinical trials to investigate the potential benefits of
loop diuretics, mostly furosemide in ischemic AKI,
Figure 3. Changes in renal tissue oxygen tension resulting from
reduced renal oxygen delivery from renal ischemia and systemic
hypoxia. Solid line, oxygen delivery. Dashed line, oxygen consump-
tion. Dotted line, renal tissue PO2. (A) Because most renal oxygen
consumption is dedicated to the reabsorption of filtered sodium,
ischemia resulting from a large decrease in preglomerular pressure
or increase in afferent arteriole resistance (arrow) decreases glomer-
ular filtration rate. This, in turn, causes a similar reduction in tubular
transport and consequent O2 consumption. Because the decrease in
glomerular filtration rate parallels the decrease in renal blood flow,
renal oxygen extraction and tissue PO2 (bottom panel) is unchanged.
(B) In systemic hypoxia (arrow), reduced O2 delivery to the kidney
occurs while renal plasma flow and glomerular filtration rate is main-
tained. This results in a mismatch between O2 delivery and metabolic
demand, and a marked decrease in tissue PO2.

generally have shown little benefit.53,54
Bagshaw et al57
reviewed 62 studies with 555 patients and found no
improvement in mortality or a reduced need for renal
replacement therapy, despite trends toward a faster
recovery. Ho and Power54
reported a meta-analysis of 11
studies with 962 patients and concluded that loop diu-
retics (including furosemide) do not reduce the need for,
or time on, renal replacement therapy or improve mortal-
ity. Other systematic reviews found similar results,
including no improvements in mortality rate or renal
function measured with creatinine clearance.
The absence of proof is not a proof of absence, and the
generally negative results from clinical trials could be
attributed to the irreversible nature of established AKI or
inappropriate clinical study design.58
Studies of patients
usually miss early causal events and generally only find
the late events of an advanced pathology that may not be
able to respond to therapeutic intervention. Clinical trials
generally are underpowered, often study high-risk patients
with high event rates, and may select inappropriate end
points.59
Furthermore, the use of diuretics, although they
increase medullary oxygen tension, may result in volume
depletion, offsetting any beneficial actions on the kidney.
However, the extensive negative literature surrounding the
prevention and treatment of AKI brings into question
whether the development of injury in AKI is more com-
plex than the mismatch between oxygen supply and oxy-
gen demand for transport in the medulla, which is
exacerbated by reduced perfusion.
Vascular Obstruction and Impaired Reﬂow: Pro and
Contra
The theory
Observations from several studies have indicated that the
true weakness of the kidney may be the susceptibility of
the renal medulla to vascular congestion during periods
of reduced perfusion.21,22,29,30
Erythrocyte aggregation
in the outer medulla, also termed vascular congestion, is
a typical finding after ischemic damage in animal21-23,60
and human kidneys (Fig. 2).25,26
Animal studies have
shown that congestion and reduced perfusion persist in
the medulla, even after blood flow to the cortex has
returned to normal.21,61
Thus, it has been proposed that
erythrocyte accumulation, predominantly but not exclu-
sively in the outer medullary capillaries, develops during
ischemia but persists after the ischemic period and pre-
vents full reperfusion of this region.21,60
The pros of the theory are that it addresses the very
obvious and well-known medullary hyperemia of the
kidney that develops during ischemia, and shows that
preventing this greatly improves subsequent renal func-
tion and morphology. The cons are that it is unclear how
many factors contribute to causing and sustaining this
feature early and later in ischemia.
Experimental ﬁndings
The success of various interventions that prevent or
relieve vascular congestion and improve renal function
support the concept that erythrocyte aggregation occur-
ring during ischemia prevents full reperfusion after
ischemia. This determines the extent of functional and
structural damage seen at early and later time points.
Studies in rats have shown that preventing vascular con-
gestion in the medulla by decreasing hematocrit21,60
or
infusing mannitol30
before the ischemia improve renal
function both early and later after the ischemic event. In
addition, reducing congestion after ischemia by increas-
ing perfusion pressure60
or retrograde high-pressure
venous flushing62
also have shown positive results to
improve renal function after ischemia.
These findings are complemented by the findings that
the degree of vascular congestion seen in the medulla
increases when ischemia is longer and when arterial
hematocrit is increased (which favors aggregation).21
Most significantly, these maneuvers that led to an
increase in vascular congestion also were associated
with greater degrees of functional deficiency, which con-
tinued for 4 weeks after the initial ischemic event. Thus,
vascular congestion, which in previously healthy animals
can persist for 1860
or 24 hours21,63
beyond the initial
ischemic event, is clearly very relevant for prolonging
the damaging effects of ischemia.
There are many theories to explain how and why vas-
cular congestion develops (leukocyte accumulation, cap-
illary leakage, venous compression, and so forth). One
finding is that the process of tubular cell swelling during
ischemia sucks up most of the surrounding fluid, leaving
the capillaries so fluid-depleted that the erythrocytes are
left as a densely aggregated sludge (Fig. 4).30
The inner
stripe of the outer medulla is probably especially suscep-
tible because of its anatomy. The interstitial space is
very small, so the tubules and capillaries are very
close,64
allowing the tubular cells to absorb nearly all of
the vascular fluid during ischemia.30
In addition, the cap-
illary network is highly branched (Fig. 1), so that this
region of naturally low blood velocity will be less able
to remobilize the erythrocyte aggregates.
The role of cell swelling and loss of vascular fluid in
the generation of vascular congestion and the loss of
renal function is confirmed by the results obtained after a
brief intrarenal infusion of mannitol. After this maneu-
ver, vascular congestion almost completely was elimi-
nated, tubular cell swelling was much reduced, and renal
function was greatly improved.30
Thus, tubular cell
swelling during ischemia is clearly one mechanism con-
tributing to the earliest development of vascular conges-
tion, but other mechanisms also may participate.
The vascular congestion that develops during ischemia
and is so prominent in the medulla is by no means unique
to this region. It has been seen to develop in the

glomerular capillaries, the cortical peritubular capillaries,
all parts of the outer medullary capillary plexus, and in
the vasa recta of the outer and inner medulla. However,
after reperfusion the capillary congestion in the other
regions mostly disappears. These findings presumably
are a result of their greater blood supply, higher perfusion
pressures and greater flow velocity. After reperfusion,
blood flow to the outer cortex is almost normal65
and
blood flow to the inner medullary papilla is not reduced,65
confirming that congestion dissipates in these regions.
Medullary congestion alone is unlikely to account for
the decreases in renal blood flow and glomerular filtra-
tion seen after ischemia. The medulla accounts for less
than 10% of total renal blood flow, and the deeper juxta-
glomerular nephrons most affected by ischemia65
only
account for a small fraction of all nephrons. Congestion,
however, may serve as a marker for other effects outside
the medulla. These could include indicating the extent of
the less obvious congestion occurring in other parts of
the kidney30
that also limit perfusion, or indicating the
extent of damage in quite different systems involved in
the pathology of renal failure.
Vascular congestion can develop and persist in two
ways. There is an accumulation and compression of
erythrocytes during ischemia and before reperfusion that
seems to reflect cell swelling because it is largely
avoided by intrarenal infusion of hypertonic mannitol.30
However, there is a further trapping of erythrocytes after
ischemia and after reperfusion that can impair reflow fur-
ther. The trapped erythrocytes seen after reperfusion
include many that were added after reperfusion, as well
as those accumulated during ischemia.66
Even when kid-
neys were kept blood-free during ischemia, reperfusion
with added erythrocytes or ghosts led to trapping and
’’no reflow,’’ which also was thought to reflect capillary
narrowing from cell swelling.67
There is very little information about whether vascu-
lar congestion in the outer medulla can occur without a
period of complete ischemia.68
However, in our hands,
vascular congestion is a common finding in rat kidneys
after surgical procedures. Reductions in blood pressure
or renal blood flow with immediate removal of the kid-
neys results in congestion without any period of com-
plete ischemia. This suggests that vascular congestion
may occur relatively easily in the renal outer medulla,
even during periods of incomplete renal ischemia or
hypoperfusion.
Clinical observations
The existence of a redness or medullary hyperemia in the
shock kidney is well established.26
As early as 1850 it
was noted that the kidneys of patients dying of acute
Bright disease were large and soft, with a pale cortex
and a hyperemic medulla. This description was con-
firmed for the crush syndrome and traumatic uremia in
World War II. Now it is considered applicable to the
shock kidney in general. Thus, pathology in the medulla,
involving a disturbance in blood flow to that region, is
not a new concept.
Some of the most relevant observations about AKI
come from renal transplantation, in which harvesting of
the donor organ always involves a period of total ische-
mia. Soon after kidney transplantation was started it
became evident that storage time was short and that
failed reperfusion leading to graft loss or delayed graft
function was a problem. Preservation strategies were
implemented to remedy this very quickly, which became
and remain standard practice. First, the organ is cooled
(to slow metabolism); second, it is flushed with cooled
perfusion solution (to accelerate cooling, but by making
it blood free it avoids the initial vascular congestion);
and, third, all perfusion solutions include impermeable
solutes (to limit cell swelling).
This early experience in kidney transplantation is very
reminiscent of the later findings with ischemic models of
Figure 4. Scanning electron micrographs of capillaries in the inner stripe of the outer medulla in tissue fixed by snap-
freezing and freeze-drying.30
Left: Normal kidney showing freely floating erythrocytes. Right: Ischemic kidneys showing
a dense erythrocyte sludge and no fluid space. Reproduced with permission from Mason et al.30

renal failure. Ischemic kidneys indicate that an early
reperfusion deficiency, that is associated with cell swell-
ing and obstructive vascular congestion, is related to
early renal dysfunction and future renal injury.
The association between anemia and AKI in patients
may appear to support a role of tissue hypoxia in the devel-
opment of AKI. Anemia has long been associated with an
increased risk of AKI and nonrecovery from AKI. Tradi-
tionally, this was thought to reflect decreased renal oxygen
delivery. However, subsequent analyses of the clinical cir-
cumstances associated with these events indicated that the
increased risk of AKI in anemia may not be owing to hyp-
oxia. Rather, the associated blood transfusions, erythropoi-
etin stimulation, and comorbid conditions likely led to the
AKI and failed recovery in these patients.69,70
Natural features that may protect against vascular
congestion
Naturally occurring mechanisms that have been found in
experimental animals may act to prevent or reduce vascu-
lar congestion in the renal medulla. Such mechanisms
may include the presence of a reduced hematocrit in med-
ullary vessels, which could lessen erythrocyte clumping,
and the presence of contractile pericytes in medullary cap-
illary walls, which can help to propel blood through the
capillaries.
The ability of erythrocytes to cause congestion in the
outer medulla after periods of ischemia is heavily influ-
enced by hematocrit.21
Therefore, it is interesting to note
that the hematocrit reported within the renal medullary
vessels is only approximately 60% of that in the general
circulation.71
Although the reasons for this are not fully
known, erythrocyte sieving has been suggested to con-
tribute. This may be facilitated by anatomic features
unique to the arterioles of the deep juxtamedullary glo-
meruli. In these nephrons, the afferent arterioles leave
the interlobular arteries at a very acute angle (Fig. 1) and
also have vascular cushions at their entrance.72
Both fea-
tures make it difficult for erythrocytes to enter into the
medullary circulation. These anatomic features, by
decreasing hematocrit and blood viscosity, may help to
protect against vascular congestion in the medulla.
Although decreasing the hematocrit would be counter-
productive if the medullary oxygen supply were criti-
cally low, it would be very useful if vascular congestion
with high-viscosity blood were the real threat.
Recent evidence from our group has suggested that
vascular pericytes in the descending vasa recta capillar-
ies may act as a defense mechanism against prolonged
medullary congestion.29
Pericytes, which are contractile
cells lining the descending vasa recta, are most dense
within the outer medullary region and contract in a peri-
staltic-like manner.73
It recently was shown that the den-
sity of pericytes in the vasa recta reflected the degree of
vascular congestion after reperfusion (fewer pericytes,
more vascular congestion).29
Furthermore, maneuvers
that decrease pericyte density increased the level of vas-
cular congestion.29
Thus, pericytes may represent an
additional physiological mechanism to prevent pro-
longed vascular congestion by helping to restore flow in
the medullary capillaries. By extension of this argument,
their loss during ischemia could contribute to vascular
congestion after ischemia.29
IMPLICATIONS FOR RESEARCH AND TREATMENT
If vascular congestion, rather than medullary hypoxia, is
the key event that initiates the early stages of renal dys-
function and tubular injury after an ischemic episode,
this has implications for both research and for treatment.
These implications for research and treatment derive
from the fact that the problem in ischemic AKI becomes
shifted from one that is primarily hypoxic in nature to
one that is primarily rheologic in nature. The sequence
of key events that underlie the vascular congestion the-
ory are that ischemia causes the congestion, congestion
fails to reverse, ischemia persists, and damage ensues, as
shown in Figure 5. This shifts the emphasis for research
and treatment.
Research Implications
The first implication is that more extensive research is
needed for understanding and preventing the events that
led to vascular congestion, which is likely to be an early
initiating event. There has been little research into the
causes and cures for vascular congestion, into mapping
its time course and location, and into testing simple
maneuvers to avoid or reduce it.
The second implication is that methods are needed to
quantify the degree and extent of tubular injury, which is
a later secondary event. Studies at later time points,
when the damage from failed reperfusion is maximized,
will help to indicate what factors promote or hinder
reperfusion once the initial ischemic event has ended.
The third implication is that animal models should be
refined to include those risk factors that are likely to
increase the damage from an ischemic insult. The roles
of pre-existing vascular damage, of pharmacologic
agents, and of toxic, inflammatory, or immunologic
influences all merit systematic investigation.
Treatment Implications
The presence of vascular congestion does have some
practical consequences. It will prolong ischemia to the
outer medullary region (and to a lesser extent to other
regions) beyond the initial ischemic insult and the resul-
tant regional and transient hypoxia may escape detection.
It also will limit the ability of any supportive treatments
to reach their intended tissue target, much as occurs with

myocardial or cerebral infarction. Similar to these condi-
tions, identifying the blood flow blockage early and
developing clinically useful methods to help prevent or
reverse vascular congestion may provide the best chance
of interrupting the events that perpetuate renal injury.
The concept that vascular congestion is the primary
driver of injury in ischemic AKI suggests that further
periods of poor perfusion should be avoided. As such,
renal vasoconstrictors should not be used when trying to
maintain blood pressure because these will tend to
reduce perfusion further. It suggests that that high-dose
furosemide is not likely to help, consistent with results
from clinical studies showing that furosemide conferred
no benefit. It also suggests that keeping the hematocrit
level low to normal may provide benefit, as would meas-
ures to increase blood fluidity.
CONCLUSIONS
The present analysis of relevant published literature relat-
ing to the topic of why the kidney is so susceptible to
ischemia, despite its high blood flow, suggests that a mis-
match between oxygen supply and oxygen demand is not
a likely cause of injury early after ischemia and that vascu-
lar congestion is more likely an initiating event. However,
delayed reperfusion, or no reflow, caused by vascular con-
gestion could well cause a later mismatch between oxygen
supply and oxygen demand. This could be seen particu-
larly when filtration resumes and tubules must transport
salts and fluid, despite the poor perfusion that persists
mainly in the outer medulla but also in other regions.
Delayed reperfusion from vascular congestion leading
to the continued low availability of oxygen and meta-
bolic substrates is clearly an incomplete and simplistic
description of the complex pathophysiology of acute
renal injury. Congestion, however, may be the earliest
event that, if prevented or reversed, avoids the subse-
quent events that contribute to renal injury. It could be
the failure to rapidly decongest, rather than the formation
of congestion itself, that is the critical event that causes
ischemic injury. Thus, vascular decongestion represents
a well-founded therapeutic target, worthy of adding to
other efforts to improve patient outcomes.
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