Uploaded by Hoàng Đặng

Pathophisiology of Ischemic Acute Tubular Necrosis

Clinical Queries: Nephrology 0101 (2012) 18–26
Contents lists available at ScienceDirect
Clinical Queries: Nephrology
January–March 2012, Vol. 1/Issue 1
j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
ISSN No.: 2211-9477
Pathophysiology of ischemic acute tubular necrosis
Jitendra Kumar*
*Senior Consultant and Head Nephrologist, Asian Institute of Medical Sciences Badkal Flyover Road, Sector 21 A, Faridabad – 121001.
a r t i c l e
i n f o
Article history:
Received 15 October 2011
Accepted 22 October 2011
Acute kidney injury
Acute tubular necrosis
a b s t r a c t
Ischemia is an important cause of acute tubular necrosis. In spite of fluctuations in hydration and blood pressure, kidney tries to auto regulate glomerular perfusion with the help of myogenic reflex, tubuloglomerular
feedback, and renin- angiotensin system. Other protective features are medullary pericytes, higher capacity
for glycolysis in medulla, and capacity of kidney to be preconditioned. Poor fluid intake or increased fluid loss,
bleeding, low cardiac output state, and sepsis-induced vasodilatation cause renal hypoperfusion. Diseased renal
vessels, old age, diabetes, nonsteroidal anti-inflammatory drug (NSAID) predispose to ischemia. When ischemia
is severe, compensatory renal mechanisms are overwhelmed and renal failure ensues. In pre-renal failure, function quickly normalizes if perfusion is restored. But with worse insult, renal tubular cells actually get injured
and necrosed. In its most extreme form, ischemia leads to bilateral renal patchy or complete cortical necrosis.
Pathophysiology of ischemic acute renal failure is not as simple as ischemia. Today it is considered an inflammatory disease. Innate and acquired immunity, tubular and endothelial factors, leukocytes, mitochondrial biogenesis, apoptosis, all are involved. Organ cross-talk of acute kidney injury (AKI) explains multiorgan involvement
and increased mortality. After a maintenance phase, restoration of tubular epithelium takes place after dedifferentiation and proliferation of surviving tubular cells. Resolving and protectins may initiate resolution.
When new tubular cell regains polarization and function, renal function gradually returns to normal. Sometimes
recovery may be incomplete. The detailed understanding of pathophysiology and underlying mediators is helping in identifying various biomarkers for early diagnosis of AKI and also in exploring novel therapeutic options.
Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Pathophysiology of ischemic acute tubular necrosis
Acute tubular necrosis (ATN) ideally refers to a specific histological
finding of necrosis of renal tubular cells, but in routine clinical practice it is also used interchangeably with acute renal failure (ARF)
which in turn refers to rapid fall in glomerular filtration rate over
hours to weeks. recently the term ‘acute kidney injury’ (AKI) is
being used in preference over ARF1 in recognition of diverse spectrum of underlying pathology, an important role of sub lethal injury
to tubular epithelial cells and recognized involvement of other
non-tubular renal cells such as endothelial cells in the pathogenesis
of this syndrome. Detailed review of the pathophysiology of AKI secondary to renal ischemia is presented in this article.
Protective mechanisms of kidney against ischemia
In normal physiological condition, in spite of fluctuations in hydration
and blood pressure, kidney tries to autoregulate glomerular perfusion,
*Corresponding author.
E-mail address: jitendra.kumar@aimsindia.co.in; jitendradivya@yahoo.co.uk
ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved.
doi: 10.1016/S2211-9477(11)70006-1
ultrafiltration pressure, and filtration rate by three major factors that
modulate either afferent or efferent arteriolar tone:
1. Myogenic reflex. This is first line of defense against fluctuations
in renal blood flow. Due to the presence of pressure receptors,
acute fall in renal perfusion pressure evoke reflex dilatation of
the afferent arteriolar smooth muscle cells which helps protect
the glomerular capillary from sudden fall in systolic pressure.2
2. Tubuloglomerular feedback.3 During conditions associated with
increased glomerular filtration rate, there is increased NaCl
delivery to macula densa. This triggers ATP release into the
surrounding extracellular space. ATP probably has a direct vasoconstrictor effect by acting on P2X1 purinoceptors on afferent
arteriolar cells; but in addition, degradation of ATP to adeno­
sine may act on afferent arteriolar A1 receptors, thereby causing
vasoconstriction. Conversely, reduced solute delivery to the
macula densa leads to blunting of this feedback causing dilatation of afferent arteriole supplying that nephron’s glomerulus.
This restores glomerular filtration to normal levels. Loop di­
uretics block tubuloglomerular feedback by interfering with
NaCl reabsorption by macula densa cells. Angiotensin II and
reactive oxygen species enhance, while nitric oxide blunts tubuloglomerular feedback.
3. Renin-angiotensin system.4 During states of reduced renal blood
flow; renin is released from granular cells of the juxtaglomerular
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
apparatus. Renin, catalyzes the conversion of angiotensinogen
to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin
II causes vasoconstriction of the efferent arteriole. This increases glomerular hydrostatic pressure and restores glomerular filtration rate (GFR).
In response to renal hypo perfusion, intrarenal biosynthesis of vasodilator prostaglandins (e.g. prostacyclin, prostaglandin E2), kallikerin
and kinins, and possibly nitric oxide (NO) is enhanced.
Thus a clever interplay (Table 1) of constriction and relaxation of
afferent and efferent arteriole helps in maintaining renal blood flow
and GFR even in face of wide fluctuation in body hydration and blood
Renal medulla is relative hypoxic in normal physiological conditions. The degree of medullary hypoxia depends on the balance between medullary blood flow and oxygen consumption in the thick
ascending loop of Henle. Pericytes attached to the descending vasa
recta, contract and control medullary blood flow.5 Different types of
autocrine and paracrine agents such as, nitric oxide, eicosanoids, and
adenosine increase medullary oxygenation by simultaneously reducing
pericyte contraction and tubular transport. Medullary cells also have a
higher capacity for glycolysis in order to reduce oxygen demand, as
compared to the cortical cell. A number of heat shock proteins, are expressed in the medulla. They assist cell survival by restoring damaged
proteins and by inhibiting apoptosis.6
Preconditioning: Kidney can be preconditioned by previous toxins
or ischemic exposure so that it is more resistant to subsequent toxins
or ischemia.7 Inducible nitric oxide synthetase, hypoxia-inducible
transcription factor8 and heat shock protein-709 are the mediators.
What makes kidney vulnerable?
In various conditions (Table 2) there is a fall in mean systemic arterial
pressure. In such situation body will try to maintain blood flow to
critical areas such as heart and brain but compromise upon relatively
‘less important’ vascular beds such as the musculocutaneous and
splanchnic circulations. This happens due to, activation of carotid sinus
and other arterial and cardiac baroreceptors which initiates a series of
neural and humoral responses (Figure 1) that include activation of the
sympathetic nervous system10 and renin–angiotensin–aldosterone
system11 and release of antidiuretic hormone.12 There is an attempt by
body to stimulate thirst and salt appetite, there is inhibition of salt loss
through sweat glands and kidneys will try to preserve salt and water.
Autoregulation normally occurs between systolic blood pressures
of 80 mmHg and 150 mmHg. When renal hypoperfusion is more severe, above mentioned compensatory renal mechanisms are overwhelmed. For example, autoregulatory dilatation of afferent arterioles is maximal at a mean systemic arterial blood pressure of about
70–80 mmHg, and hypotension below this level is associated with a
precipitous decline in glomerular ultrafiltration pressure and GFR.13
Despite renal autoregulation, a number of nervous and humoral
extrinsic factors can alter renal hemodynamics.14 Erratic changes in
the resistance of afferent and efferent arterioles, together with alterations in mesangial cell contraction and relaxation can result in disproportionate or even contrasting changes in renal perfusion and
GFR. For example very high levels of angiotensin II, as are found in
patients with marked circulatory failure, provoke constriction of both
afferent and efferent arterioles, thus negating the relatively selective
effect of low levels of this peptide on efferent arteriolar resistance.15
Diseased renal arteriole, of atherosclerosis, hypertension, diabetes,
renovascular disease, old age, and progressive kidney disease disturbs these mechanisms and interfere with renal autoregulation.16
Various pharmacological interventions in day-to-day practice also
disturb these protective mechanisms.17,18
Ischemic injury is most prominent in the S3 segment of the proximal tubule and the medullary portion of the thick ascending limb
of the loop of Henle. These segments of the tubule are particularly
sensitive to ischemia because of high rates of active ATP-dependent
solute transport and because of their location in the outer medulla.
Major blood supply of kidney goes to cortex whereas outer medulla
Table 1
Interplay of constriction and relaxation of afferent and efferent arteriole manipulating renal blood flow and net ultrafiltration pressure and common mediators involved in this.
Arteriole resistance
Renal blood flow
Net UF pressure
Increased afferent
Decreased afferent
Increased efferent
Decreased efferent
Renal sympathetic nerves, adenosine, calcineurine inhibitor, NSAID
High protein diet, nitric oxide, ANP, PGE2/I2, calcium channel blockers
Angiotensin II, endothelin 1
ACEI: angiotensin converting enzyme inhibitor, ANP: atrial natriuretic peptide, ARB: angiotensin receptor blocker, DRI: direct renin inhibitor, NSAID: nonsteroidal anti-inflammatory
drug, UF: ultrafiltration.
Table 2
List of various etiological factors which may be responsible for renal ischemia.
Decreased intake
Increased fluid loss
No access to fluid—dehydration
Poor fluid replacement in admitted patients
Psychiatric disorders
Gastrointestinal fluid loss—diarrhea and vomiting
Hemorrhage—trauma, surgery, obstetric bleeding
Renal fluid loss—diuretics, nephrogenic diabetes insipidus
Other losses and extravascular sequestration—burns, pancreatitis, severe hypoalbuminemia, hyperthermia, crush syndrome
Low cardiac output
Cardiac cause
Non cardiac cause
Valvular heart disease, myocardial disease, pericardial tamponade
Pulmonary embolism, impaired venous return as in abdominal compartment syndrome or positive pressure ventilation
Increased capacitance
Systemic vasodilation
Sepsis, antihypertensives, anaphylaxis
Renal vasoconstriction
Hypercalcemia, cocaine, catecholamines, ergotamines, drugs such as calcineurin inhibitors and amphotericin B, unknown mechanism
in hepatorenal syndrome, sepsis
Impaired autoregulation
Non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, Direct renin
Systemic vasodilatation and
intrarenal vasoconstriction
Infection and sepsis
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
and medullary rays get blood mainly from vasa recta. Due to
Countercurrent exchange by the medullary capillaries, oxygen diffuses
from descending to ascending vasa recta, bypassing the deeper
regions. Consequently hypoxia in medulla is augmented. The partial
pressure of oxygen normally decreases from 50 mmHg in the cortex
to 10 mmHg in the inner medulla.19
dysfunction of increasing severity, namely, risk of renal dysfunction,
injury to the kidney and failure of kidney function, and two outcome
categories: loss of function, and end-stage kidney.22
The spectrum of ischemia-induced, acute kidney injury
A variety of etiological conditions (Table 2) will lead to renal ischemia.
Kidneys are vulnerable to ischemia as explained above. Various protective mechanisms are evoked by kidney to maintain perfusion but
In response to ischemia, kidney tries to protect itself from injury by
evoking various protective mechanisms. For the benefit of entire body,
there is tendency to retain fluid and salt and at the same time, excrete
maximum nitrogenous waste by producing highly concentrated urine.
But with ongoing severity of ischemia, these protective mechanisms
are overwhelmed and renal injury ensues. The degree of ischemia will
decide the degree of renal injury and scope of recovery (Flowchart 1).
Milder ischemia leads to pre-renal failure.13 As per the definition
here renal parenchyma is not damaged. When renal perfusion is restored, ischemia is reversed and kidneys return back to normal function.
In patients of gastrointestinal fluid loss or hemorrhage when aggressive
rehydration is achieved, the initial renal abnormalities quickly normalize and the condition is said to be pre-renal. When ischemia is more
severe, for example when all conditions responsible for pre-renal failure
are severe and not reversed quickly, renal tubular cells actually get
injured.20 Kidney evokes reparative work and after some time tubular structure is restored leading to normalization of kidney function.
In its most extreme form, ischemia leads to bilateral renal patchy
or complete cortical necrosis. Such events are seen more in developing world in conditions such as post-partum hemorrhage with late
referral or following septic abortion.21 Here there is incomplete recovery of cellular damage and the condition progresses to chronic
kidney disease or end-stage renal disease.
When translated into acute dialysis quality improvement initiative
(ADQI) proposed RIFLE diagnostic classification scheme, a spectrum
of clinical finding is appreciated which includes three levels of renal
The pathophysiology of ischemia-induced, acute tubular
necrosis (Flowchart 2)
Conditions causing renal
ischemia (Table 2)
Failure of protective
factors (Table 3)
Renal injury
manifestationsmetabolic, organ
Quickly reversible when renal
perfusion is restored
e.g. Gastrointestinal fluid loss
with rapid rehydration
Acute tubular necrosis
Renal tubular cells
are injured
Tubular structured restored
after reparative work
e.g. Following major
cardiovascular surgery
Patchy cortical necrosis
Patches of cortex
are necrosed
Incomplete recovery
leading to CKD
e.g. Following post-partum
hemorrhage with late referral
Cortical necrosis
Entire cortex
necrosed bilaterally
Leads to end stage
renal disease
Flowchart 1 Spectrum of injuries found in ischemic acute kidney disease.
Restoration of
tubular epithelium
Restoration of
tubular function
Flowchart 2 Sequence of events in pathophysiology of ischemic acute tubular
Pre-renal failure
Renal parenchyma
is not damaged
Inflammation, vascular,
tubular factors
e.g. After septic abortion
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
as the insult increase in severity, renal function compromises. There
are various pathological and pharmacological conditions which increases the susceptibility of kidney (Table 3). If renal perfusion is restored quickly before any injury has occurred renal function quickly
normalize. A good analogy is transient ischemic attacks as seen in
neurology. However more severe ischemia leads to damage of tubular cells. Apart from simple ischemia-related injury, role of inflammation,23 apoptosis24 and other mediators25 are increasingly being
considered important. During the maintenance phase restoration of
tubular epithelium takes place. When this new tubular cell regains
polarization and function, renal function gradually returns to normal. The detail understanding of pathophysiology is helping in identifying various biomarkers for early diagnosis of AKI and also in
exploring novel therapeutic options.26 A brief description of all involved factors is discussed in following paragraphs.
Conditions causing renal ischemia
Table 2 enlists the various etiological factors which may be responsible for renal ischemia. Hypovolemia could be true as seen in poor
fluid intake or increased fluid loss. Decreased fluid intake, either due
to in availability of fluid, inability to swallow or iatrogenic fluid deficit
or increased fluid loss through urine and gastrointestinal system
cause true fluid deficit. Some times in spite of volemia, renal perfusion is impaired due to effective or functional hypovolemia. This occurs in low cardiac output state, third space losses or due to systemic
vasodilation. Various humoral and pharmacological agents may cause
renal hypoperfusion by causing renal vasoconstriction or by impairing
renal auto regulation. Sometimes the insult is multifactorial, for example a patient of infected pancreatitis may have endotoxin-induced
systemic vasodilation, third space fluid loss in peritoneal cavity, poor
fluid intake, low cardiac output due to abdominal compartment syndrome, and inotrope-related renal vasoconstriction.
Contributing to renal ischemia
There are various factors which make kidneys vulnerable to ischemia
as discussed above. However, at least in animal model an inherent
resistance to tubular injury has been seen. For example in rat model
even severe hypotension with blood pressure < 50 mmHg for 2–3 hours
did not cause hypotension. It is possible that combined injurious
mechanisms are required and presence of some contributory factors
may augment the ischemic process in a particular case. Table 3 enumerates some of the conditions which when present, predisposes
kidney to acute injury in presence of renal ischemia.
Imbalance between vasoconstrictors and dilators
The net effect of above mentioned influence is an imbalance between vasoconstrictors and dilators causing failure of protection and
renal ischemia. Possible mediators being nitric oxide, endothelin,
atrial natriuretic peptide (ANP), angiotensin II, dopamine, eicosanoids, platelet-activating factors, dopamine and calcium channels.14
Role of inflammation
Pathophysiology of ischemic ARF is not as simple as ischemia. Today
it is considered an inflammatory disease.28 Inflammation plays an
important role in entire course of AKI, right from initiation to extension through repair. There is numerous evidence of endothelial injury, leukocyte infiltration in the kidney and the generation of
inflammatory mediators. Anoxic injury to tubular cells, vascular
smooth muscle cells, and endothelial cells, leads to disruption of
actin cytoskeleton.29 Endothelial-erythrocyte interactions lead to
sludging of erythrocytes. The combination of hypoxic injury, changes
in endothelial cell morphology, and heightened interactions between red blood cell (RBC) and endothelium leads to the extension
of the initial renal injury. Innate immunity as well as adaptive immunity, both are involved and an understanding of these inflammatory
pathways provide scope for therapeutic intervention.
Innate immunity:30 It has early response in inflammation and is
independent of foreign antigen. Up-regulation of natural killer cell in
AKI is an example of innate immunity. Activation of complement is
another. Latter can cause direct injury of the renal tubular epithelial
cells, and signaling through complement receptors. Recently role of
Toll like receptors (TLR2 and 4) have been understood. In mice
model, absence of this receptor has anti-inflammatory response giving functional protection.
Several proinflammatory cytokines31 (such as tumor necrosis factor alpha, interleukins IL-6 and IL-1b) and chemokines (such as MCP-1,
IL-8, RANTES) are generated within the kidney and promote the infiltration of leukocytes.
In early inflammation there is margination of neutrophils32 to vascular endothelium. Selectins, integrins, P-selectin and adhesion molecules are up-regulated. There is slowing of leukocytes at the site of
injury by selectins. Modulation of the selectin33 pathway can alter
outcome of ARF through neutrophil dependent and independent34
manner. Firm adhesion of leukocytes occurs by the interactions of integrins with intercellular adhesion molecule-1 (ICAM-1). In experimental models, blockage of these factors such as blockade of the
integrin CD11/CD18,35 treatment with anti-ICAM-1 (or CD54)36 monoclonal antibodies, treatment with a-MSH37 which inhibits interleukin-8 and ICAM-1 induction, Blockage of platelet-activating factor
(PAF),38 all have been found to be protective. But the exact mechanism is much more complex, beyond neutrophils, whose role is now
considered to be only modest.
Mononuclear leukocytes39 may also have a role. T-cell associated
cytokines are produced in experimental models. Above mentioned
adhesion molecules targeted for neutrophil blockade also mediate
T-cell adhesion. Experimental ischemia-reperfusion injury may be
Table 3
Some of the conditions, which predispose kidney to acute injury, in presence of renal ischemia.
Contributing factor
Mechanism of action
Advanced age
Diseased afferent arterioles and impaired autoregulation, loss of interstitial HO-1-positive cells
Renovascular disease
Diseased afferent arterioles and impaired autoregulation
Hypertensive nephrosclerosis
Diseased afferent arterioles and impaired autoregulation
Diabetic nephropathy
Diseased afferent arterioles and impaired autoregulation
Circulatory failure
Very high levels of angiotensin II provoke constriction of both afferent and efferent arterioles
Inhibit protective vasodilator prostaglandin
Underlying chronic kidney disease
GFR is maintained in part by prostaglandin-mediated hyperfiltration through remnant nephrons
ACEI/ARB/DRI in presence of bilateral renal artery stenosis or
Here, intraglomerular pressure and GFR are dependent on angiotensin II induced compensatory
unilateral stenosis in a solitary functioning kidney18
Multifactorial. Peripheral vasodilation-induced hypotension. Impaired renal perfusion due to
neurohormonal factors. Inflammatory mediators
ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, DRI: direct renin inhibitor, GFR: glomerular filtration rate, NSAID: nonsteroidal antiinflammatory drug.
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
ameliorated by T-cell depletion or blockade of T-cell co stimulatory
pathways. In addition, CD4-deficient mice (helper T cells), double
CD4/CD8 knockout and T cell deficient (nu/nu) knockout mice have
renal protection.40 Adoptive transfer of T cells from wild type animals into the (nu/nu) mice restored ischemic injury, proving the
role of the T cell in ischemic injury.41 Interferon-g (IFN-g) and the
B7-CD28 pathway may be involved. Hit-and-run hypothesis suggests initial T cell offence in the initiation of ARF.42 Different T cell
subset behave differently. Th1 phenotype of T cells is deleterious,
and the Th2 phenotype is protective. Macrophages also may have
role in AKI.
Mitochondrial biogenesis and its attendant processes enhance
metabolic pathways such as fatty acid oxidation and increase antioxidant defense mechanisms that ameliorate injury from aging,
tissue hypoxia, and glucose or fatty acid overload, all of which contribute to the pathogenesis of acute and chronic kidney disease.
Mediators involved are peroxisome proliferator-activated receptors
(PPAR) in the kidney, PPARg co-activators and their modulators such
as SIRT1.43 The available data indicate that these pathways will be
fruitful areas for study in the modification of renal disease.
Vascular factors
After failure of initial compensatory increase in renal flow, when
ATN has been established, renal blood flow actually falls by 30–50%
due to vasoconstriction. Tubuloglomerular feedback3 and other
vasoconstrictors may actually be other protective mechanisms to
decrease the glomerular filtration and ATP-dependent tubular transport and thus oxygen demand in ongoing ischemia.
Various involved vasoconstrictors are angiotensin II, endothelin 1,
adenosine, thromboxane A2, prostaglandin H2, leukotrienes C4 and
D4, and sympathetic nerve stimulation, increased cytosolic calcium
content in afferent arterioles and disruption of the actin cytoskeleton in vascular smooth muscle impairing autoregulation. Recently,
20-hydroxyeicosatetraenoic acid (20-HETE) has been found to play
an important role in ischemic reperfusion model of AKI.44
Endothelial cell
They play an important role in the development of ARF. Damaged endothelium is unable to regulate local blood flow, cell migration into
tissues, and prevention of coagulation,45,46 leading to continued
ischemic injury following the initial insult.
Actin filament bundles make up the cytoskeleton which support
periphery of the endothelial cell.47 They shrink in the setting of ATP
depletion. The assembly and disassembly of actin filaments is regulated by a family of actin-binding proteins. The actin depolymerizing
factor/cofilin (ADF) family of proteins is known to regulate actin dynamics and play a role in the changes to the actin cytoskeleton during ischemia.48 Animals with renal ischemia have functional
protection by the transplanted endothelial cells.49 Ischemic insult
changes the interactions between endothelial cells and inflammatory cells. P- and E-selectin are up-regulated on endothelial cells in
the setting of ischemic damage as is ICAM-1.50,51
Tubular factors
Both the S3 segment of proximal tubule and medullary thick ascending limb contribute to the inflammatory response in AKI.52 Ischemia
as well as reperfusion injures tubular cells. Mediators of tubular cell
injury include reactive oxygen species (ROS), intracellular calcium
influx, nitric oxide, phospholipase A2, complement, TNF-a and beta,
MCP-1, IL-6, IL-8, RANTES, ENA-78 and cell mediated cytotoxicity.
The ROS may be derived from local sources or from infiltrating leukocytes. In animal models of ischemic ATN, a variety of methods that
inhibit ROS protect against renal injury.53 The initial insult to the tubular epithelial cell depletes cellular ATP, which, in turn, leads to disruption of the apical actin cytoskeleton as seen with endothelial
cells. Disruption of the actin cytoskeleton results in movement of integrins from basolateral positions to the apical membrane, leading to
impaired cell matrix adhesion and cell detachment.54 Tubular cells are
attached to the tubular basement membrane by alpha 3 and beta 1 integrins, which recognize RGD (arginine-glycine-aspartate) sequences
in matrix proteins. Loss of integrin polarity,55 particularly the b1 integrins, away from the basolateral membrane to the apical domain
can lead to detachment of viable cells from the basement membrane
and sloughing of cells into the tubular lumen.54 Activation of the
cysteine protease calpain can degrade actin-binding proteins such as
spectrin and ankyrin. This leads to abnormal translocation of Na+, K+ATPase and other proteins from the basolateral membrane to the
cytoplasm or apical membranes. Thus there is loss of tubular cell polarity. The loss of the basolateral Na, K-ATPase decreases proximal
tubular sodium reabsorption and increases the fractional excretion
of sodium (FENa) contributing to tubuloglomerular feedback and
drop in GFR.54 Sloughed proximal tubular cells can bind to RGD sequences in Tamm Horsfall protein (THP), resulting in cast formation
and intratubular obstruction. In models of ischemic AKI, the elevation in tubular pressures may be inhibited by synthetic RGD peptides, mitigating the obstructive process.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)
and its receptor, fibroblast growth factor-inducible 14 (TWEAK-Fn14),
are newly understood mediators. They are widely expressed and are
involved in both injury and repair. They have paracrine and autocrine
Apoptosis which means programmed cell death is found to be active both during initial tubular injury and also during repair work in
regulating number and morphology of cells-240.
Morphology of renal injury in acute tubular necrosis
Actual necrosis of tubular epithelial cells is a less common than cellular injury and dysfunction.57 Various types of injury are—apoptosis,
loss of cells, gaps in the tubular architecture,58 denuded basement
membrane, and cells sloughing into tubular lumens. There is luminal
obstruction due to the accumulation of tubular casts containing THP
along with exfoliated tubular cells, remnants of shed brush border,
and other cellular debris (Figure 1).59 Tubular injury is most severe in
the outer medulla involving S3 segments of the proximal tubule and
the medullary thick ascending limb of the distal nephron. Other
areas of injury can be seen within the renal cortex, involving both
proximal and distal segments of the nephron. Ischemic injury causes
rapid loss of cytoskeletal integrity and cell polarity. There is damage
to the brush border of the proximal tubules. The microvilli of brush
border are shortened or completely absent and can be found collecting in the tubular lumen.60
Pathophysiology of manifestations of ischemic
acute tubular necrosis
Fall in glomerular filtration rate
There is a profound decrease in the GFR, even in the absence of major
light microscopic injury. In a typical AKI, only 10 to 15% of tubular
cells are injured but fall in GFR is disproportionately high due to various mechanisms. The first mechanism for this is a direct fall in GFR
caused by afferent arteriolar vasoconstriction due to endothelial cell
injury leading to an imbalance in vasoactive substances, with a predominance of vasoconstrictive activity.59 The second mechanism is
tubular back leakage. Ischemia causes damage and loss of epithelial
cells exposing basement membranes and also loss of tight junctions
between tubular cells. Tubular filtrate then starts leaking into the interstitium and gets reabsorbed in systemic circulation causing net
reduction in the GFR. The third mechanism is tubular obstruction
which is discussed above. Fall of GFR cause decreased salt and water
excretion leading to mild hypertension, pulmonary effusion or even
pulmonary edema.
Urine volume is a relatively unhelpful parameter in differential
diagnosis of AKI which may be non-oliguric (urine output > 400 mL/
day), oliguric (urinary output < 400 mL/day), or anuric (urinary output < 100 mL/day). As per RIFLE classification scheme,22 AKI may be
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
classified as per urine volume criteria. Urine output < 0.5 mL/kg/hr
for 6 hours indicate risk and for 12 hours indicate injury whereas
output < 0.3 mL/kg/hr for 24 hours or anuria for 12 hours indicate
Hyaline casts are formed in concentrated urine from normal constituents of urine, principally THP secreted by epithelial cells of the
loop of Henle. Hence the urinary sediment is typically acellular in
pre-renal AKI and may be transparent. Pigmented ‘muddy brown’
granular casts and tubule epithelial cell casts are characteristic of
ischemic or nephrotoxic ATN. Casts may be absent, in approximately
20–30% of patients. And there is a poor correlation between the severity of renal failure and the amount of debris in the urine sediment. The RBC casts almost always indicate acute glomerular injury.
Renal failure indices
In renal ischemia body will try to conserve sodium and excrete nitrogen waste in limited amount of concentrated fluid. Na is reabsorbed
avidly from glomerular filtrate as a consequence of suppression of
ANP secretion, activation of renal nerves and the renin-angiotensinaldosterone axis, and local changes in peritubular hemodynamics.
When injury is established, Na reabsorption is inhibited as a result of
tubule cell injury. Creatinine is reabsorbed to a much smaller extent
than Na in both conditions. The fractional excretion of Na+ (FENa)
which relates Na clearance to creatinine clearance is < 1.0%, frequently < 0.01% in pre-renal failure, whereas this is usually > 2.0% in
patients with established ischemic AKI.
Serum biochemistry
The AKI is complicated by hyperkalemia, hyponatremia, hyper phosphatemia, hypocalcemia, hypermagnesemia, and rise of nitrogenous
waste products.61 There is impaired excretion of K. Metabolic acidosis promotes K efflux from cells. Fluid retention due to low GFR, excessive water ingestion or administration of hypotonic saline or
isotonic dextrose solutions causes hyponatremia. Mild hyperphosphatemia is also very common. In hypercatabolic states of rhabdomyolysis, hemolysis, or tumor lysis, hyperphosphatemia (upto
20 mg/dL) and hyperkalemia and hyperuricemia is very common because of their release from damaged cells.
Binding of calcium and phosphorus especially when product of
their value exceeds 70 can lead to hypocalcemia. Skeletal resistance
to the actions of parathyroid hormone, reduced levels of 1,25dihydroxyvitamin D, and Ca sequestration in injured tissues are other
contributory factors.62 Mild asymptomatic hypermagnesemia due to
impaired excretion is usual in oliguric AKI. Hypokalemia and hypomagnesemia are unusual but may occur in non oliguric ATN
caused by aminoglycosides, cisplatin, or amphotericin B, presumably
by causing epithelial cell injury in the thick ascending limb of the
loop of Henle where reabsorption of K and Mg occurs. Asymptomatic
hyperuricemia with figures upto 12–15 mg/dL is common due to failure to excrete uric acid. In conditions such as tumor lysis syndrome
there may be an overproduction of uric acid. Ratio of urinary urea
and creatinie is < 0.75 in former and > 1 in latter.63 Around 50 and
100 mmol/day of fixed non-volatile acids is produced due to normal
metabolism. In AKI this acid load is not excreted leading to metabolic
acidosis, typically with a widening of the serum anion gap.64 Lactic
acidosis due to tissue hypoperfusion, liver disease and sepsis augment the problem.
Involvement of other organ systems
Acute renal failure is now considered a systemic disease. Clamping of
the renal artery in rats increased pulmonary vascular permeability
with microvascular inflammation and both leukocyte and RBC sludging65 giving evidence for direct AKI induced distant organ dysfunction also known as organ cross-talk. The lung injury is blunted in rats
when treated by CNI-1493, which blocks the release of macrophagederived inflammatory products. Lung injury is also associated with
a down regulation of pulmonary epithelial sodium channels, Na/
K-ATPase, and aquaporin-5.66 Kidney injury affects bone marrow causing anemia and immune dys-regulation through, of serum granulocyte colony-stimulating factor (G-CSF).67 Further, AKI can also cause
biosynthetic abnormalities in liver, transporter abnormalities in gut
and inflammation and apoptosis in myocardium. Understanding this
organ cross-talk68 of AKI may explain increased mortality and may
also help in finding therapeutic targets.
Reparative process of acute tubule necrosis
After established kidney injury, a maintenance phase of 1 to 2 week
duration follows, during which parenchymal injury is established
and GFR stabilizes at a value of 5–10 mL/min. In most (but not all)
conditions this period is oliguric. After this, repair and regeneration
of renal tissue starts. There is a gradual increase in urine output
so called diuretic phase. Sometimes recovery is delayed for 1 to 11
months in conditions such as atheroembolic renal disease, systemic
auto-immune disease, renovascular diseases, and scleroderma.69
Resolvin (Rv) and protectins (PD) are two new identified families
of naturally occurring n-3 fatty acid metabolite.70 Their production
may be an endogenous mechanism of the kidney to control inflammation and initiate resolution of inflammation. Recovery from ATN
requires the restoration of tubular cells and coverage of denuded tubular basement membrane. Surviving tubular cells that remain adherent to basement membrane undergo repair. Later new epithelial
cell spread and migrate to cover the exposed areas of basement
membrane.71 Restored tubular cells may come from a subpopulation
of stem or progenitor cell-derived from bone marrow.72 Some studies
have suggested that mesenchymal stem cells may locate to areas of
tubular injury and transform into proximal tubular cells.73 But some
conclude that bone marrow does not contribute directly to the replacement of cells. Rather it may have paracrine effect that facilitate
repair, potentially by reducing inflammation.74 Thus the restoration
of tubular cell number is due to the dedifferentiation and proliferation of surviving tubular cells.75
A number of growth factors have been implicated in the proliferative response, including insulin-like growth factor 1 (IGF-1)76 erythropoietin77 and hepatocyte growth factor.78 A hypoxic environment
increases the transcription of genes involved in angiogenesis, erythropoiesis and anaerobic energy metabolism. Hypoxia-inducible factor (HIF) is thought to play a major role in this process.79 Newly
formed de differentiated cells matures to become polarized tubular
epithelial cells and gradually the normal renal function is restored.75
Although traditionally it was thought that recovery is complete, now
this is being realized that that may not be the case always.80 After
severe injury, the proximal tubule cellular response is impaired with
its proliferative response altered due to cell cycle arrest at the G2/M
phase of the cell cycle, resulting in generation of profibrotic factors
including cytokines, growth factors and matrix proteins. This leads
to fibrosis and attribute myofibroblast expansion to perivascular and
interstitial fibroblasts finally causing CKD.81
There has been enormous interest in studying the pathophysiology of ischemic AKI. They help in understanding the mechanism of
injury and repair and they also give insight into development of bio­
markers for diagnosis and search of various therapeutic options.
Several animal models have been developed for experimental studies. This includes clamping of one or both kidneys, cold ischemia
with warm reperfusion achieved by removing a kidney, placing it on
ice, and then re-implanting it and mouse cardiac arrest model. Some
of various experimental studies done in this regard in last 1 year is
summarized in Table 4.
Ischemic ATN actually refers to a spectrum of kidney hypoperfusion
and injury and is better called AKI. When protective mechanism of
kidney against ischemia is overwhelmed by various etiological agent,
with or without underlying contributory factors, AKI results. In its
most mild form the pathology is functional and with quick restoration of perfusion kidney quickly regains normal function. This is
called pre-renal AKI. With more severe insult, tubular necrosis and
even cortical necrosis may occur. Traditionally it has been thought
that, after a maintenance period which is commonly characterized
Kidney homogenates from rats exposed to mild renal ischemia-reduced cell surface NHE3
protein expression in opossum kidney cells in vitro, whereas homogenates from animals with
moderate-to-severe ischemia reduced both total NHE3 protein and mRNA
Hypoxia-induced inflammatory responses were IKKb/NF-kB-dependent. Knockdown of IKKb by siRNA
suppressed the transcription IKKb/NF-kB-mediated inflammatory mediators in tumor necrosis
factor-a or CoCl(2)-treated tubular epithelial cells, and decreased CoCl(2)-induced cell death
In a rat model (IR), treatment with SS-31 (a mitochondria-targeted tetrapeptide that can scavenge
mitochondrial ROS and inhibit mitochondrial permeability transition), protected mitochondrial
structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis
and necrosis of tubular cells, and abrogated tubular dysfunction
N-acetylcysteine (NAC) and ebselen (E), significantly decreased malondialdehyde and nitrite/nitrate,
levels and increased superoxide dismutase and glutathione peroxidase activities. They are able to
ameliorate IRI of the kidney by decreasing oxidative and nitrosative stresses and increasing free
radical scavenger properties. Combination of NAC and E prevents kidney damage more than when each
drug is used alone
Modified citrus pectin (MCP) treated mice demonstrated reduced galectin-3 and renoprotection.
In association with decreased renal fibrosis, macrophages, pro-inflammatory cytokine expression
and apoptosis. Other renal galectins, galectin-1 and -9, were unchanged
In Heat shock protein 70 (Hsp70) knockout, mice. The kidney cortical Hsp70 content inversely
correlated with tubular injury, apoptosis, and organ dysfunction after injury
Failure of Hemeoxygenase-1 (HO-1) induction following renal IRI worsens structural and
functional injury in older mice
In pig model, the levels of TNF-a in the plasma and the levels of TNF-a and IL-10 in the renal
cortex were lower in the EPO group compared with the sham group
In pig model (post cardiac surgery) endothelin A receptor antagonist administration reverses
endothelial dysfunction, regional tissue hypoxia, and proximal tubular epithelial cell stress
In sheep model hyperdynamic sepsis, with or without hypotension, creatinine clearance decreased despite
increasing renal blood flow. Intrarenal Nw-nitro-L-arginine methyl ester infusion reduced renal blood flow
but did not improve creatinine clearance
Hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type
proximal tubule epithelial cells, but these responses were markedly blunted by MyD88 (adaptor protein
of toll-like receptor 4). Treatment with pituitary adenylate cyclase-activating polypeptide (PACAP38)
before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis
In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 hr, (MMPs).
Apoptosis and necrosis, were evident but the kidneys of MMP-2 (-/-) mice showed minimal injury
In a rat ischemia-reperfusion (I-R) model of AKI, freshly isolated, uncultured adipose tissue-derived
stem and regenerative cells (ADRCs) therapy drastically reduced mortality, serum creatinine
and histological effects
AKI: acute kidney injury, EPO: erythropoietin.
S. No.
Table 4
Summary of various experimental studies on pathophysiology of acute kidney injury during last 1 year (2011).
ADRCs could offer an autologous treatment strategy for patients who are at high-risk for
AKI during planned interventions
Matrix metalloproteinases (MMPs), especially MMP-2 have a pathogenic role in
ischemia-reperfusion AKI
TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88
signaling. The renoprotective effect of PACAP in AKI involves both MyD88-dependent
and -independent pathways
Septic AKI is not the result of decreased renal blood flow nor is
it improved by nonspecific nitric oxide synthase inhibition
Antagonism of the endothelin-1 A receptor prevents AKI
EPO attenuated the renal dysfunction by immune modulatory effects
Hemeoxygenase-1-positive renal macrophages mediate HA-induced protection in aged mice
Increasing Hsp70 either before or after ischemic injury preserves
renal function by attenuating AKI
MCP may reduce renal injury in the long term, perhaps via
carbohydrate binding-related functions of galectin-3
N-acetylcysteine (NAC) and ebselen (E) prevents renal ischemic injury
SS-31 is protective against ischemia
Small interfering RNA (siRNA)-based treatment can prevent ischemic AKI
Transferable factor(s) mediate the ischemia-reperfusion
injury-induced decrease in NHE3 of the kidney
Ref. No.
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
by oligurea kidney enters a diuretic phase reparative process restores
tubular anatomy and function. However the case may not be as simple as this and some of the cases may progress to chronic kidney disease and ESRD (end-stage renal disease).
Apart from vasomotor and vasoconstrictor-related hypoperfusion
a more complex pathophysiological process is involved. Various mediators with active inputs from renal tubule, endothelium and leukocyte come into complex interplay. Understanding them has led to
development of various new biomarkers for the diagnosis, and also
has opened a window for exploring various therapeutic options.
The authors wish to thank Dr. Gaurav Sahai for helping in preparing
the manuscript and Dr. Divya Kumar for help in preparing the list of
Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of
an initiative to improve outcomes in acute kidney injury. Criti Care 2007;
Gilmore JP, Cornish KG, Rogers SD, Joyner WL. Direct evidence for myogenic autoregulation of the renal microcirculation in the hamster. Circ Res 1980;47:
Vallon V. Tubuloglomerular feedback and the control of glomerular filtration
rate. News Physiol Sci 2003;18:169–74.
Schnermann J, Briggs J. Function of the juxtaglomerular apparatus: control of
glomerular hemodynamics and renin secretion. In: The Kidney: Physiology and
Pathophysiology 3rd ed, Seldin DW, Giebisch G, eds. Philadelphia: Lippincott,
Williams and Wilkins 2000.
Pallone TL, Zhang Z, Rhinehart K. Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 2003;284:F253–66.
Neuhofer W, Beck FX. Cell survival in the hostile environment of the renal
medulla. Annu Rev Physiol 2005;67:531–55.
Boventere JY. Kidney ischemic preconditioning. Corr opin Nephrol Hypertens
Bernhardt WM, Campean V, Kany S, et al. Preconditional activation of hypoxia
inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol
Jo SK, Ko GJ, Boo CS, et al. Heat preconditioning attenuates renal injury in
ischemic ARF in rats: role of heat-shock protein 70 on NF-kappa B-mediated
inflammation and on tubular cell injury. J Am Soc Nephrol 2006;17:3082–92.
Kon V, Yared A, Ichikawa I. Role of renal sympathetic nerves in mediating hypo­
perfusion of renal cortical microcirculation in experimental congestive heart
failure and acute extracellular fluid volume depletion. J Clin Invest 1985;76:
Blume A, Kaschina E, Unger T. Angiotensin II type 2 receptors: signalling and
pathophysiological role. Curr Opin Nephrol Hypertens 2001;10:239–46.
Aisenberry GA, Handleman WA, Arnold P, et al. Vascular effects of arginine vasopressin during fluid deprivation in the rat. J Clin Invest 1981;67:961–8.
Badr KF, Ichikawa I. Prerenal failure: a deleterious shift from renal compensation
to decompensation. N Engl J Med 1988;319:623–9.
Loutzenhiser R, Griffin K, Williamson G, Bidani A. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol 2006;290:R1153–67.
Hall JE, Guyton AC, Jackson TE, et al. Control of glomerular filtration rate by
renin-angiotensin system. Am J Physiol 1977;233:F366–72.
Lameire N, Nelde A, Hoeben H, et al. Acute renal failure in the elderly. Geriatr
Nephrol Urol 1999;9:153–65.
Bennett WM, Henrich WL, Stoff JS. The renal effects of non-steroidal antiinflammatory drugs: summary and recommendations. Am J Kidney Dis 1996;29:
Textor SC. Renal failure related to angiotensin-converting enzyme inhibitors.
Semin Nephrol 1997;17:67–76.
Heyman SN, Rosen S, Brezis M. The renal medulla: life at the edge of anoxia.
Blood Purif 1997;15:232–42.
Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the
intensive care unit: the PICARD experience. Kidney Int 2004;66:1613–21.
Ansari MR, Laghari MS, Solangi KB. Acute renal failure in pregnancy: one year
observational study at Liaquat University Hospital, Hyderabad. J Pak Med Assoc
Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome
measures, animal models, fluid therapy and information technology needs: the
Second International Consensus Conference of the Acute Dialysis Quality Initiative
(ADQI) Group. Crit Care 2004;8:R204–12.
Bonventre JV. Pathophysiology of acute kidney injury: roles of potential inhibitors of inflammation. Contrib Nephrol 2007;156:39–46.
Ueda N, Kaushal GP, Shah SV. Apoptotic mechanisms in acute renal failure.
Am J Med 2000;108:403–15.
25. Akcay A, Nguyen Q, Edelstein CL. Mediators of inflammation in acute kidney
injury. Mediators Inflamm 2009;13:70–2. [Epub 2010 Feb 21]
26. Pelte CH, Chawla LS. Novel therapeutic targets for prevention and therapy of sepsis associated acute kidney injury. Curr Drug Targets 2009;10:1205–11.
27. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004;351:
28. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease?
Kidney Int 2004;66:480.
29. Kwon O, Phillips CL, Molitoris BA. Ischemia induces alterations in actin filaments
in renal vascular smooth muscle cells. Am J Physiol Renal Physiol 2002;282:
30. Gonçalves GM, Zamboni DS, Câmara NO. The role of innate immunity in septic
acute kidney injuries. Shock 2010;34(Suppl 1):22–6.
31. Lee DW, Faubel S, Edelstein CL. Cytokines in acute kidney injury (AKI). Clin
Nephrol 2011;76:165–73.
32. Thornton MA, Winn R, Alpers CE, et al. An evaluation of the neutrophil as a
mediator of in vivo renal ischemic-reperfusion injury. Am J Pathol 1989;135:
33. Nemoto T, Burne MJ, Daniels F, et al. Small molecule selectin ligand inhibition
improves outcome in ischemic acute renal failure. Kidney Int 2001;60:
34. Burne MJ, Rabb H. Pathophysiological contributions of fucosyltransferases in
renal ischemia reperfusion injury. J Immunol 2002;169:2648–52.
35. Rabb H, Medniola C, Dietz J, et al. Role of CD11a and CD11b in ischemic acute
renal failure in rats. Am J Physiol 1994;267:F1052–58.
36. Haug C, Colvin R, Delmonico F, et al. Phase 1 trial of immunosuppression with
anti-ICAM (CD54) mAb in renal allograft recipients. Transplantation (Baltimore)
37. Jo SK, Yun SY, Chang KH, et al. Alpha-MSH decreases apoptosis in ischaemic acute
renal failure in rats: possible mechanism of this beneficial effect. Nephrol Dial
Transplant 2001;16:1583–91.
38. Riera M, Torras J, Herrero I, et al. Neutrophils accentuate renal cold ischemiareperfusion injury. Dose-dependent protective effect of a platelet-activating factor receptor antagonist. J Pharmacol Exp Ther 1997;280:786–94.
39. Lemay S, Rabb H, Postler G, et al. Prominent and sustained up-regulation of
gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemiareperfusion injury. Transplantation 2000;69:959–63.
40. Rabb H, Daniels F, O’Donnell M, et al. Pathophysiological role of T lymphocytes in
renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 2000;279:
41. Burne MJ, Daniels F, El Ghandour A, et al. Identification of the CD4(+) T cell as
a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001;108:
42. Ascon DB, Lopez-Briones S, Liu M, et al. Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury.
J Immunol 2006;177:3380–7.
43. Weinberg JM. Mitochondrial biogenesis in kidney disease. J Am Soc Nephrol
2011;22:431–6. [Epub 2011 Feb 25]
44. Roman RJ, Akbulut T, Park F, Regner KR. HETE in acute kidney injury. Kidney Int
45. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002;62:1539–49.
46. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension
phase of acute renal failure. Kidney Int 2004;66:496–9.
47. Hinshaw DB, Burger JM, Miller MT, et al. ATP depletion induces an increase in the
assembly of a labile pool of polymerized actin in endothelial cells. Am J Physiol
48. Bamburg JR. Proteins of the ADF/cofilin family: essential regulators of actin
dynamics. Annu Rev Cell Dev Biol 1999;15:185–230.
49. Brodsky SV, Yamamoto T, Tada T, et al. Endothelial dysfunction in ischemic acute
renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol
50. Eppihimer MJ, Russell J, Anderson DC, et al. Modulation of P-selectin expression in the postischemic intestinal microvasculature. Am J Physiol 1997;273:
51. Molitoris BA, Marrs J. The role of cell adhesion molecules in ischemic acute renal
failure. Am J Med 1999;106:583–92.
52. Lieberthal W, Nigam SK. Acute renal failure. Relative importance of proximal vs
distal tubular injury. Am J Physiol 1998;275:F623–32.
53. Nath KA, Norby SM. Reactive oxygen species and acute renal failure. Am J Med
54. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc
Nephrol 2006;17:1503–20.
55. Woroniecki R, Ferdinand JR, Morrow JS, et al. Dissociation of spectrin-ankyrin
complex as a basis for loss of Na-K-ATPase polarity after ischemia. Am J Physiol
Renal Physiol 2003;284:F358–64.
56. Weinberg JM. TWEAK-Fn14 as a mediator of acute kidney injury. Kidney Int
57. Racusen LC. Pathology of acute renal failure: structure/function correlations.
Adv Renal Replacement Ther 1997;4:3–16.
58. Racusen LC. The morphologic basis of acute renal failure. In: Acute Renal Failure,
Molitorids BA, Finn WF, eds. New York: WB Saunders 2001:1–12.
59. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002;62:1539–49.
60. Wangsiripaisan A, Gengaro PE, Edelstein CL, et al. Role of polymeric TammHorsfall protein in cast formation: oligosaccharide and tubular fluid ions. Kidney
Int 2001;59:932–40.
J. Kumar / Clinical Queries: Nephrology 0101 (2012) 18–26
61. May RC, Stivelman JC, Maroni BJ. Metabolic and electrolyte disturbances in
acute renal failure. In: Acute Renal Failure 3rd ed, Lazarus JM, Brenner BM, eds.
New York: Churchill Livingston 1993:107–17.
62. Pietrek J, Kokot F, Kuska J. Serum 25-hydroxyvitamin D and parathyroid hormone
in patients with acute renal failure. Kidney Int 1978;13:178–85.
63. Tungsanga K, Boonwichit D, Lekhakula A, et al. Urine uric acid and urine creatine
ratio in acute renal failure. Arch Intern Med 1984;144:934–7.
64. Palmer BF. Approach to fluid and electrolyte disorders and acid–base problems.
Prim Care 2008;35:195–213.
65. Kramer AA, Postler G, Salhab KF, et al. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 1999;
66. Rabb H, Wang Z, Nemoto T, et al. Acute renal failure leads to dysregulation of
lung salt and water channels. Kidney Int 2003;63:600–6.
67. Zhang Y, Woodward VK, Shelton JM, et al. Ischemia-reperfusion induces G-CSF
gene expression by renal medullary thick ascending limb cells in vivo and in vitro.
Am J Physiol Renal Physiol 2004;286:F1193–201.
68. Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: the role of the kidney. Curr
Opin Crit Care 2009;15:481–7.
69. Chu JK, Folkert VW. Renal function recovery in chronic dialysis patients. Semin
Dial 2010;23:606–13. [Epub 2010 Dec 20]
70. Serhan CN, Hong S, Gronert K, et al. Resolvins: a family of bioactive products of
omega-3 fatty acids transformation circuits initiated by aspirin treatment that
counter proinflammation signals. J Exp Med 2002;196:1025–37.
71. Liu KD, Brakeman PR. Renal repair and recovery. Crit Care Med 2008;36:S187–92.
72. Masereeuw R. Contribution of bone marrow-derived cells in renal repair after
acute kidney injury. Minerva Urol Nefrol 2009;61:373–84.
73. Humphreys BD, Bonventre JV. Mesenchymal stem cells in acute kidney injury.
Annu Rev Med 2008;59:311–25.
74. Stagg J. Immune regulation by mesenchymal stem cells: two sides to the coin.
Tissue Antigens 2007;69:1–9.
75. Duffield JS, Park KM, Hsiao LL, et al. Restoration of tubular epithelial cells during
repair of the postischemic kidney occurs independently of bone marrow–
derived stem cells. J Clin Invest 2005;115:1743–55.
76. Hirschberg R, Kopple J, Lipsett P, et al. Multicenter clinical trial of recombinant
human insulin-like growth factor I in patients with acute renal failure. Kidney Int
77. Bernhardt WM, Eckardt KU. Physiological basis for the use of erythropoietin in
critically ill patients at risk for acute kidney injury. Curr Opin Crit Care 2008;
78. Homsi E, Janino P, Amano M, et al. Endogenous hepatocyte growth factor attenuates inflammatory response in glycerol-induced acute kidney injury. Am J
Nephrol 2009;29:283–91. [Epub 2008 Sep 29]
79. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell
Biol 2004;5:343–54.
80. Chawla LS. Acute kidney injury leading to chronic kidney disease and long-term
outcomes of acute kidney injury: the best opportunity to mitigate acute kidney
injury? Contrib Nephrol 2011;174:182–90.
81. Yang L, Humphreys BD, Bonventre JV. Pathophysiology of acute kidney injury to
chronic kidney disease: maladaptive repair. Contrib Nephrol 2011;174:149–55.
82. Di Sole F, Hu MC, et al. The reduction of Na/H exchanger-3 protein and transcript
expression in acute ischemia-reperfusion injury is mediated by extractable
tissue factor(s). Kidney Int 2011 Aug 3. doi: 10.1038/ki.2011.229. [Epub ahead
of print]
83. Wan X, Yang J, Xing L, et al. Inhibition of IkB Kinase b attenuates hypoxia-induced
inflammatory mediators in rat renal tubular cells. Transplant Proc 2011;43:
84. Szeto HH, Liu S, Soong Y, et al. Mitochondria-targeted peptide accelerates ATP
recovery and reduces ischemic kidney injury. J Am Soc Nephrol 2011;22:1041–52.
[Epub 2011 May 5]
85. Kizilgun M, Poyrazoglu Y, Oztas Y, et al. Beneficial effects of N-acetylcysteine and
ebselen on renal ischemia/reperfusion injury. Ren Fail 2011;33:512–7. [Epub 2011
May 6]
86. Kolatsi-Joannou M, Price KL, Winyard PJ, Long DA. Modified citrus pectin reduces
galectin-3 expression and disease severity in experimental acute kidney injury.
PLoS One 2011;6:e18683.
87. Wang Z, Gall JM, Bonegio RG, et al. Induction of heat shock protein 70 inhibits
ischemic renal injury. Kidney Int 2011;79:861–70.
88. Ferenbach DA, Nkejabega NC, McKay J, et al. The induction of macrophage
hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney
Int 2011;79:966–76. [Epub 2011 Jan 19]
89. Sølling C, Christensen AT, Krag S, et al. Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemiareperfusion injury. Acta Anaesthesiol Scand 2011;55:185–95.
90. Patel NN, Toth T, Jones C, et al. Prevention of post-cardiopulmonary bypass acute
kidney injury by endothelin A receptor blockade. Crit Care Med 2011;39:793–
91. Ishikawa K, Bellomo R, May CN. The impact of intrarenal nitric oxide synthase
inhibition on renal blood flow and function in mild and severe hyperdynamic
sepsis. Crit Care Med 2011;39:770–6.
92. Li M, Khan AM, Maderdrut JL, Simon EE, Batuman V. The effect of PACAP38 on
MyD88-mediated signal transduction in ischemia-/hypoxia-induced acute
kidney injury. Am J Nephrol 2010;32:522–32. [Epub 2010 Oct 28]
93. Kunugi S, Shimizu A, Kuwahara N, et al. Inhibition of matrix metalloproteinases
reduces ischemia-reperfusion acute kidney injury. Lab Invest 2011;91:170–80.
[Epub 2010 Oct 18]
94. Feng Z, Ting J, Alfonso Z, et al. Fresh and cryopreserved, uncultured adipose
tissue-derived stem and regenerative cells ameliorate ischemia-reperfusioninduced acute kidney injury. Nephrol Dial Transplant 2010;25:3874–84. [Epub
2010 Oct 4]