# Importance and Limits of Ischemia in Renal Partial Surgery: Experimental and Clinical Research

Authors: Fernando P. Secin
Journal: Advances in Urology
 (2008)

---

## Abstract

Introduction. The objective is to determine the clinical and experimental evidences of the renal responses to warm and cold ischemia, kidney tolerability, and available practical techniques of protecting the kidney during nephron-sparing surgery. Materials and methods. Review of the English and non-English literature using MEDLINE, MD Consult, and urology textbooks. Results and discussion. There are three main mechanisms of ischemic renal injury, including persistent vasoconstriction with an abnormal endothelial cell compensatory response, tubular obstruction with backflow of urine, and reperfusion injury. Controversy persists on the maximal kidney tolerability to warm ischemia (WI), which can be influenced by surgical technique, patient age, presence of collateral vascularization, indemnity of the arterial bed, and so forth. Conclusions. When WI time is expected to exceed from 20 to 30 minutes, especially in patients whose baseline medical characteristics put them at potentially higher, though unproven, risks of ischemic damage, local renal hypothermia should be used.


---

## Body

## 1. Introduction

Nephron-sparing surgery  in the oncologic  setting  entails
complete local resection of a renal tumor while leaving the largest possible
amount of normal functioning parenchyma in the involved kidney. Different surgical techniques can be employed
for performing partial nephrectomy, but all of them require adherence to basic
principles of early vascular control, avoidance of ischemic renal damage with
complete tumor excision with free margins, precise closure of the collecting
system, careful hemostasis, and closure with or without tamponading of the
renal defect with adjacent fat, fascia, or any available artificial sealant [1, 2].Observance of all
these principles is extremely important, however, prevention of ischemic renal damage is a
key to the final success of the procedure. Ischemia is the leading cause of
postoperative acute and chronic renal failure in patients undergoing nephron
sparing surgery, for which no specific medical treatment modality has been
established to date.By the same token, surgeons need to apply transitory
occlusion of the renal artery as it not only diminishes intraoperative
parenchymal bleeding but also improves visualization and facilitates access to
intrarenal structures by causing the kidney to contract and by reducing renal
tissue fullness. Surgeons performing this approach require an understanding of
renal responses to warm ischemia (WI) and available methods of protecting the
kidney when the period of arterial occlusion exceeds normal parenchyma
tolerability [3].In order to decrease the exposure of the spared parenchyma to
ischemia, the surgeon should have a complete preoperative and intraoperative assessment of the
relationship of the tumor and its vascular supply to the collecting system and
adjacent normal renal parenchyma [4–6].There is no question
that the less the better, whenever the philosophy to preserve as much
functioning renal tissue as possible is followed. This manuscript seeks to
determine the clinical and experimental evidences of the renal responses to warm
and cold ischemia, kidney tolerability, and available practical techniques of
protecting the kidney when the period of arterial occlusion surpasses that
which may be safely tolerated during renal nephron sparing surgery.


## 2. Material and Methods

Biomedical and related databases were queried including MEDLINE, MD
Consult, and urology textbooks. Manuscripts and library archives were retrieved
from the Nathan Cummings Center, Memorial Sloan-Kettering Cancer Center, NY,
USA.A Medline search in combination with additional references of
non-Medline-indexed journals included the following key words:
“nephron-sparing surgery,” “partial nephrectomy,” “warm ischemia and
kidney,” and “ischemia time and kidney,” as well as links to related articles.
Non-English articles and letters to editors were reviewed as well. These
references formed the basis of the article. Following selection and deletion
based on relevance of the subject and importance of the studies, a library of
115 references remained.


## 3. Results and Discussion

### 3.1. Intraoperative Renal Ischemia: Pathophysiology of Injury

In recent years, there have been significant insights into
the pathophysiologic process of renal ischemia [7, 8]. Ischemic insult to the
kidney often results in damage to cells of nephron and renal vasculature. Cells
are lost through the processes of necrosis and apoptosis, inevitably leading to
renal failure. Renal failure is characterized by a decline in glomerular
filtration rate, retention of nitrogenous waste products, perturbation of extra
cellular fluid volume, and electrolyte and acid-base homeostasis. Renal failure
is only diagnosed when these pathophysiologic perturbations are advanced enough
to manifest biochemical abnormalities in the blood. The pathophysiologic response
to cell death dictates the prevailing level of renal functional impairment [9].
Therefore, a clear understanding of the extent of post ischemic kidney damage
and associated inflammation is needed to prevent this hitherto intractable
condition, which will ultimately impact on overall survival [10].For understanding and didactic  purposes, three
interrelated main mechanisms through which ischemia damages the kidney are
herein described based on a recent review by Abuelo [7]. One
mechanism is merely vascular, caused by persistent vasoconstriction and an
abnormal response of endothelial cells to compensatory means. The second is
obstructive, where soughed tubular epithelial cells and brush-border-membrane
debris form casts that obstruct tubules, and glomerular filtrate leaks from the
tubular lumen across denuded tubular walls into capillaries and the circulation
(back-leak) causing a reduction in the “effective” GFR, where the latter is
defined as the rate at which filtrate is delivered into final urine. The third
has to do with reperfusion injury after blood flow is restored [7, 11].


#### 3.1.1. Vascular Mechanism

Both animal and human studies have found that a multi-inflammatory
response is involved in ischemia/reperfusion injury of the kidney [12]. The
inflammatory reaction incurred after an ischemic insult precipitates more
damage to the tissue and impedes intrarenal blood flow caused by
vasoconstriction and vascular congestion, leading to a vicious cycle [13].This damage mainly takes place in endothelial cells of the
peritubular capillaries, especially in the outer medulla, which is marginally
oxygenated under normal circumstances. This oxidant injury, together with a
shift in the balance of vasoactive substances toward vasoconstrictors such as endothelin,
results in vasoconstriction, congestion, hypoperfusion, and expression of
adhesion molecules. The expression of adhesion molecules, in turn, initiates
leukocyte infiltration, augmented by proinflammatory and chemotactic cytokines
generated by ischemic tubular cells [7].Inciting stimuli induce kidney macrophages and probably
renal parenchymal cells to release inflammatory cytokines, such as tumor
necrosis factor-α (TNF-α) and interleukin-1 (IL-1). TNF-α and IL-1 promote
renal parenchymal damage by directly inducing apoptosis in epithelial cells,
recruitment of neutrophils that release reactive oxygen metabolites and
proteases, and up regulating adhesion receptors on endothelial cells and
leukocytes [14, 15]. These cytokines also stimulate renal cortical epithelial
cells to release the chemoattractant interleukin-8 [16, 17]. The arrival of
additional leukocytes obstructs the microcirculation and releases more cytotoxic
cytokines, reactive oxygen species, and proteolytic enzymes, which damage the
tubular cells [7].Endothelial injury results in cell swelling and enhanced
expression of cell adhesion molecules. This, together with leukocyte
activation, leads to enhanced leukocyte-endothelial cell interactions, which
can promote injury and swelling of the endothelial cell. Endothelial swelling
contributes to the production of local factors promoting vasoconstriction and
adds to the effects of vasoconstriction and tubule cell metabolism by
physically impeding blood flow, perpetuating that vicious cycle [18].Heterogeneity of intrarenal blood flow contributes to the
pathophysiology of ischemic renal failure. An imbalance between the vasodilator
nitric oxide and the vasoconstrictor endothelin impairs medullary blood flow,
especially in the outer medulla, where tubules have high oxygen requirements,
resulting in cellular injury due to a mismatch between oxygen delivery and
demand. Endothelial activation and injury together with increased leukocyte-endothelial
cell interactions and activation of coagulation pathways may have a greater effect
on outer medullary ischemia than arteriolar vasoconstriction, as there can be
markedly impaired oxygen delivery to the outer medulla despite adequate renal
blood flow [18].The arteriolar response to vasoactive substances can also
be altered during endothelial injury. The basal tone of arterioles is increased
in post ischemic kidneys as well as their reactivity to vasoconstrictive
agents. These arterioles also have decreased vasodilatory responses compared
with arterioles from normal kidneys. Alterations in local levels of
vasoconstrictors (angiotensin II, thromboxane A2, leukotrienes,
adenosine, endothelin-1) have been implicated in abnormal vascular tone [19].
Angiotensin II seems to play a key role by activating endothelin B or
prostaglandin H2-thromboxane A2 receptors. Systemic endothelin-1 levels increase with ischemia, and
administration of antiendothelin antibodies or endothelin receptor antagonists
has been reported to protect against ischemia-reperfusion injury [20].
Saralasin, an angiotensin II receptor antagonist, could also attenuate
angiotensin II vasoconstricting effect [21]. Nitric oxide, an
endothelial-derived relaxing factor, plays a theoretical protective role
against ischemic renal injury, by means of its vasodilatory effect and by decreasing
endothelin expression and secretion in the vascular endothelium. Of interest,
endothelial nitric oxide synthase is inhibited during endothelial injury [22].
A combination therapy consisting of
5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl
cysteine (NAC), drugs that inhibit the induction of proinflammatory cytokines
and nitric oxide synthase, and block tumor necrosis factor-alpha induced
apoptotic cell death,  has shown to attenuate
ischemia-reperfusion injury in a canine model of autologous renal
transplantation [23]. Early studies showed no conclusive evidence that
vasodilators (such as diltiazem or dopamine) or other compounds have any clinical
utility in either preventing or treating ischemic renal failure in humans thus
far [24–26]. More
recently, however, the highly selective dopamine type 1 agonist fenoldopam
mesylate [27] and the antianginal medication trimetazidine [28] appeared to aid
in restoring renal function to baseline values in patients with prolonged WI
time. Further research is needed.


#### 3.1.2. Obstructive Mechanism

Normally, the cells are bathed in an extra cellular
solution high in sodium and low in potassium. This ratio is maintained by a
sodium pump (Na+-K + ATPase pump) which uses much of the adenosine triphosphate
(ATP) energy derived from oxidative phosphorylation. ATP is required for the
cellular sodium pump to maintain a high intracellular concentration of
potassium and a low concentration of sodium. The sodium pump effectively makes
Na+ an impermeant outside the cell that counteracts the colloidal osmotic
pressure derived from intracellular proteins and other anions [29].The ischemic insult causes a failure of oxidative
phosphorylation and ATP depletion, leading to malfunctioning of the sodium pump.
When the sodium pump is impaired, sodium chloride and water
passively diffuse into the cells, resulting in cellular swelling and the
“no-reflow” phenomenon after renal reperfusion. Cellular potassium and
magnesium are lost, calcium is gained, anaerobic glycolysis and acidosis occur,
and lysosomal enzymes are activated. This results in cell death. During
reperfusion, hypoxanthine, a product of ATP degradation, is oxidized to
xanthine with the formation of free radicals that cause further cell damage [29].
(See later.)As mentioned, the mechanism whereby ischemia and oxygen
depletion injure tubular cells starts with ATP depletion, which activates a
number of critical alterations in metabolism, causing cytoskeletal disruption
and loss of those properties that normally render the tubule cell monolayer
impermeable to certain components of filtrate. Cytoskeletal disruption causes
not only loss of brush-border microvilli and cell junctions but also
mislocation of integrins and the sodium pump from the basal surface to the
apical surface.In addition, impaired sodium reabsorption by injured
tubular epithelial cells increases the sodium concentration in the tubular
lumen. The increased intratubular sodium concentration polymerizes Tamm-Horsfall protein,
which is normally secreted by the loop of Henle, forming a gel and contributing
to cast formation. As a result, brush-border membranes and cells slough
obstruct tubules downstream. As mentioned before, these debris form casts that
obstruct tubules, and glomerular filtrate leaks from the tubular lumen across
denuded tubular walls into capillaries and the circulation (back-leak) causing
a reduction in the “effective” GFR. ATP depletion also activates harmful
proteases and phospholipases, which, with reperfusion, cause oxidant injury to
tubular cells, the so-called reperfusion injury [7].


#### 3.1.3. Reperfusion Injury

WI insult followed by restoration of blood flow to the
ischemic tissue frequently results in a secondary reperfusion injury. Despite WI causing significant renal dysfunction,
reperfusion injury has been shown to be as damaging or even more detrimental
than renal ischemia itself, producing an inflammatory response that worsens
local kidney damage and leads to a systemic insult [30, 31].The reperfusion injury can be mediated by several
mechanisms including the generation of reactive oxygen species, cellular
derangement, microvessel congestion and compression, polimorphonuclear
(PMN)-mediated damage, and hypercoagulation. Reperfusion with the resulting
reintroduction of molecular oxygen of constricted microvessels leads to
congestion and red cell trapping. This vascular effect can reduce renal blood
flow by as much as 50% [32].During the reperfusion period, superoxide production in
the kidney is markedly enhanced by the transformation of xanthine dehydrogenase
to xanthine oxidase and the increase in free electrons in mitochondria,
prostaglandin H, and lipoxygenase with the coexistence of NAD(P)H  and
infiltrated neutrophils. Superoxide raises the following chain reactions,
producing hydroxyl radicals or other reactive oxygen species (ROSs), or interacts with nitric oxide (NO),
which is produced by macrophage inducible NO synthase, generating a highly
toxic radical peroxynitrite. These ROS and NO derived species consume tissue
antioxidants and decrease organ reducing activity [33].The exact magnitude of reperfusion injury is still
unclear. Some authors state that the role of free radicals mediated injury in
kidneys may not be as significant as in other organs given the low relative
activity of renal xanthine oxidase compared with the high endogenous activity
of superoxide dismutase [29].Notwithstanding, nicaraven
(N,N9-propylenebisnicotinamide), a drug that may actively trap free radicals
and prevent vascular constriction due to lipid peroxide [34] and edaravone
(3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186), a synthetic free radical
scavenger, have shown in vitro experiments to protect endothelial cells against
ischemic injury in different organs, including ischemically damaged kidneys
[35, 36]. Clinical studies are eagerly awaited.


## 3.1. Intraoperative Renal Ischemia: Pathophysiology of Injury

In recent years, there have been significant insights into
the pathophysiologic process of renal ischemia [7, 8]. Ischemic insult to the
kidney often results in damage to cells of nephron and renal vasculature. Cells
are lost through the processes of necrosis and apoptosis, inevitably leading to
renal failure. Renal failure is characterized by a decline in glomerular
filtration rate, retention of nitrogenous waste products, perturbation of extra
cellular fluid volume, and electrolyte and acid-base homeostasis. Renal failure
is only diagnosed when these pathophysiologic perturbations are advanced enough
to manifest biochemical abnormalities in the blood. The pathophysiologic response
to cell death dictates the prevailing level of renal functional impairment [9].
Therefore, a clear understanding of the extent of post ischemic kidney damage
and associated inflammation is needed to prevent this hitherto intractable
condition, which will ultimately impact on overall survival [10].For understanding and didactic  purposes, three
interrelated main mechanisms through which ischemia damages the kidney are
herein described based on a recent review by Abuelo [7]. One
mechanism is merely vascular, caused by persistent vasoconstriction and an
abnormal response of endothelial cells to compensatory means. The second is
obstructive, where soughed tubular epithelial cells and brush-border-membrane
debris form casts that obstruct tubules, and glomerular filtrate leaks from the
tubular lumen across denuded tubular walls into capillaries and the circulation
(back-leak) causing a reduction in the “effective” GFR, where the latter is
defined as the rate at which filtrate is delivered into final urine. The third
has to do with reperfusion injury after blood flow is restored [7, 11].


### 3.1.1. Vascular Mechanism

Both animal and human studies have found that a multi-inflammatory
response is involved in ischemia/reperfusion injury of the kidney [12]. The
inflammatory reaction incurred after an ischemic insult precipitates more
damage to the tissue and impedes intrarenal blood flow caused by
vasoconstriction and vascular congestion, leading to a vicious cycle [13].This damage mainly takes place in endothelial cells of the
peritubular capillaries, especially in the outer medulla, which is marginally
oxygenated under normal circumstances. This oxidant injury, together with a
shift in the balance of vasoactive substances toward vasoconstrictors such as endothelin,
results in vasoconstriction, congestion, hypoperfusion, and expression of
adhesion molecules. The expression of adhesion molecules, in turn, initiates
leukocyte infiltration, augmented by proinflammatory and chemotactic cytokines
generated by ischemic tubular cells [7].Inciting stimuli induce kidney macrophages and probably
renal parenchymal cells to release inflammatory cytokines, such as tumor
necrosis factor-α (TNF-α) and interleukin-1 (IL-1). TNF-α and IL-1 promote
renal parenchymal damage by directly inducing apoptosis in epithelial cells,
recruitment of neutrophils that release reactive oxygen metabolites and
proteases, and up regulating adhesion receptors on endothelial cells and
leukocytes [14, 15]. These cytokines also stimulate renal cortical epithelial
cells to release the chemoattractant interleukin-8 [16, 17]. The arrival of
additional leukocytes obstructs the microcirculation and releases more cytotoxic
cytokines, reactive oxygen species, and proteolytic enzymes, which damage the
tubular cells [7].Endothelial injury results in cell swelling and enhanced
expression of cell adhesion molecules. This, together with leukocyte
activation, leads to enhanced leukocyte-endothelial cell interactions, which
can promote injury and swelling of the endothelial cell. Endothelial swelling
contributes to the production of local factors promoting vasoconstriction and
adds to the effects of vasoconstriction and tubule cell metabolism by
physically impeding blood flow, perpetuating that vicious cycle [18].Heterogeneity of intrarenal blood flow contributes to the
pathophysiology of ischemic renal failure. An imbalance between the vasodilator
nitric oxide and the vasoconstrictor endothelin impairs medullary blood flow,
especially in the outer medulla, where tubules have high oxygen requirements,
resulting in cellular injury due to a mismatch between oxygen delivery and
demand. Endothelial activation and injury together with increased leukocyte-endothelial
cell interactions and activation of coagulation pathways may have a greater effect
on outer medullary ischemia than arteriolar vasoconstriction, as there can be
markedly impaired oxygen delivery to the outer medulla despite adequate renal
blood flow [18].The arteriolar response to vasoactive substances can also
be altered during endothelial injury. The basal tone of arterioles is increased
in post ischemic kidneys as well as their reactivity to vasoconstrictive
agents. These arterioles also have decreased vasodilatory responses compared
with arterioles from normal kidneys. Alterations in local levels of
vasoconstrictors (angiotensin II, thromboxane A2, leukotrienes,
adenosine, endothelin-1) have been implicated in abnormal vascular tone [19].
Angiotensin II seems to play a key role by activating endothelin B or
prostaglandin H2-thromboxane A2 receptors. Systemic endothelin-1 levels increase with ischemia, and
administration of antiendothelin antibodies or endothelin receptor antagonists
has been reported to protect against ischemia-reperfusion injury [20].
Saralasin, an angiotensin II receptor antagonist, could also attenuate
angiotensin II vasoconstricting effect [21]. Nitric oxide, an
endothelial-derived relaxing factor, plays a theoretical protective role
against ischemic renal injury, by means of its vasodilatory effect and by decreasing
endothelin expression and secretion in the vascular endothelium. Of interest,
endothelial nitric oxide synthase is inhibited during endothelial injury [22].
A combination therapy consisting of
5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl
cysteine (NAC), drugs that inhibit the induction of proinflammatory cytokines
and nitric oxide synthase, and block tumor necrosis factor-alpha induced
apoptotic cell death,  has shown to attenuate
ischemia-reperfusion injury in a canine model of autologous renal
transplantation [23]. Early studies showed no conclusive evidence that
vasodilators (such as diltiazem or dopamine) or other compounds have any clinical
utility in either preventing or treating ischemic renal failure in humans thus
far [24–26]. More
recently, however, the highly selective dopamine type 1 agonist fenoldopam
mesylate [27] and the antianginal medication trimetazidine [28] appeared to aid
in restoring renal function to baseline values in patients with prolonged WI
time. Further research is needed.


### 3.1.2. Obstructive Mechanism

Normally, the cells are bathed in an extra cellular
solution high in sodium and low in potassium. This ratio is maintained by a
sodium pump (Na+-K + ATPase pump) which uses much of the adenosine triphosphate
(ATP) energy derived from oxidative phosphorylation. ATP is required for the
cellular sodium pump to maintain a high intracellular concentration of
potassium and a low concentration of sodium. The sodium pump effectively makes
Na+ an impermeant outside the cell that counteracts the colloidal osmotic
pressure derived from intracellular proteins and other anions [29].The ischemic insult causes a failure of oxidative
phosphorylation and ATP depletion, leading to malfunctioning of the sodium pump.
When the sodium pump is impaired, sodium chloride and water
passively diffuse into the cells, resulting in cellular swelling and the
“no-reflow” phenomenon after renal reperfusion. Cellular potassium and
magnesium are lost, calcium is gained, anaerobic glycolysis and acidosis occur,
and lysosomal enzymes are activated. This results in cell death. During
reperfusion, hypoxanthine, a product of ATP degradation, is oxidized to
xanthine with the formation of free radicals that cause further cell damage [29].
(See later.)As mentioned, the mechanism whereby ischemia and oxygen
depletion injure tubular cells starts with ATP depletion, which activates a
number of critical alterations in metabolism, causing cytoskeletal disruption
and loss of those properties that normally render the tubule cell monolayer
impermeable to certain components of filtrate. Cytoskeletal disruption causes
not only loss of brush-border microvilli and cell junctions but also
mislocation of integrins and the sodium pump from the basal surface to the
apical surface.In addition, impaired sodium reabsorption by injured
tubular epithelial cells increases the sodium concentration in the tubular
lumen. The increased intratubular sodium concentration polymerizes Tamm-Horsfall protein,
which is normally secreted by the loop of Henle, forming a gel and contributing
to cast formation. As a result, brush-border membranes and cells slough
obstruct tubules downstream. As mentioned before, these debris form casts that
obstruct tubules, and glomerular filtrate leaks from the tubular lumen across
denuded tubular walls into capillaries and the circulation (back-leak) causing
a reduction in the “effective” GFR. ATP depletion also activates harmful
proteases and phospholipases, which, with reperfusion, cause oxidant injury to
tubular cells, the so-called reperfusion injury [7].


### 3.1.3. Reperfusion Injury

WI insult followed by restoration of blood flow to the
ischemic tissue frequently results in a secondary reperfusion injury. Despite WI causing significant renal dysfunction,
reperfusion injury has been shown to be as damaging or even more detrimental
than renal ischemia itself, producing an inflammatory response that worsens
local kidney damage and leads to a systemic insult [30, 31].The reperfusion injury can be mediated by several
mechanisms including the generation of reactive oxygen species, cellular
derangement, microvessel congestion and compression, polimorphonuclear
(PMN)-mediated damage, and hypercoagulation. Reperfusion with the resulting
reintroduction of molecular oxygen of constricted microvessels leads to
congestion and red cell trapping. This vascular effect can reduce renal blood
flow by as much as 50% [32].During the reperfusion period, superoxide production in
the kidney is markedly enhanced by the transformation of xanthine dehydrogenase
to xanthine oxidase and the increase in free electrons in mitochondria,
prostaglandin H, and lipoxygenase with the coexistence of NAD(P)H  and
infiltrated neutrophils. Superoxide raises the following chain reactions,
producing hydroxyl radicals or other reactive oxygen species (ROSs), or interacts with nitric oxide (NO),
which is produced by macrophage inducible NO synthase, generating a highly
toxic radical peroxynitrite. These ROS and NO derived species consume tissue
antioxidants and decrease organ reducing activity [33].The exact magnitude of reperfusion injury is still
unclear. Some authors state that the role of free radicals mediated injury in
kidneys may not be as significant as in other organs given the low relative
activity of renal xanthine oxidase compared with the high endogenous activity
of superoxide dismutase [29].Notwithstanding, nicaraven
(N,N9-propylenebisnicotinamide), a drug that may actively trap free radicals
and prevent vascular constriction due to lipid peroxide [34] and edaravone
(3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186), a synthetic free radical
scavenger, have shown in vitro experiments to protect endothelial cells against
ischemic injury in different organs, including ischemically damaged kidneys
[35, 36]. Clinical studies are eagerly awaited.


## 3.1.1. Vascular Mechanism

Both animal and human studies have found that a multi-inflammatory
response is involved in ischemia/reperfusion injury of the kidney [12]. The
inflammatory reaction incurred after an ischemic insult precipitates more
damage to the tissue and impedes intrarenal blood flow caused by
vasoconstriction and vascular congestion, leading to a vicious cycle [13].This damage mainly takes place in endothelial cells of the
peritubular capillaries, especially in the outer medulla, which is marginally
oxygenated under normal circumstances. This oxidant injury, together with a
shift in the balance of vasoactive substances toward vasoconstrictors such as endothelin,
results in vasoconstriction, congestion, hypoperfusion, and expression of
adhesion molecules. The expression of adhesion molecules, in turn, initiates
leukocyte infiltration, augmented by proinflammatory and chemotactic cytokines
generated by ischemic tubular cells [7].Inciting stimuli induce kidney macrophages and probably
renal parenchymal cells to release inflammatory cytokines, such as tumor
necrosis factor-α (TNF-α) and interleukin-1 (IL-1). TNF-α and IL-1 promote
renal parenchymal damage by directly inducing apoptosis in epithelial cells,
recruitment of neutrophils that release reactive oxygen metabolites and
proteases, and up regulating adhesion receptors on endothelial cells and
leukocytes [14, 15]. These cytokines also stimulate renal cortical epithelial
cells to release the chemoattractant interleukin-8 [16, 17]. The arrival of
additional leukocytes obstructs the microcirculation and releases more cytotoxic
cytokines, reactive oxygen species, and proteolytic enzymes, which damage the
tubular cells [7].Endothelial injury results in cell swelling and enhanced
expression of cell adhesion molecules. This, together with leukocyte
activation, leads to enhanced leukocyte-endothelial cell interactions, which
can promote injury and swelling of the endothelial cell. Endothelial swelling
contributes to the production of local factors promoting vasoconstriction and
adds to the effects of vasoconstriction and tubule cell metabolism by
physically impeding blood flow, perpetuating that vicious cycle [18].Heterogeneity of intrarenal blood flow contributes to the
pathophysiology of ischemic renal failure. An imbalance between the vasodilator
nitric oxide and the vasoconstrictor endothelin impairs medullary blood flow,
especially in the outer medulla, where tubules have high oxygen requirements,
resulting in cellular injury due to a mismatch between oxygen delivery and
demand. Endothelial activation and injury together with increased leukocyte-endothelial
cell interactions and activation of coagulation pathways may have a greater effect
on outer medullary ischemia than arteriolar vasoconstriction, as there can be
markedly impaired oxygen delivery to the outer medulla despite adequate renal
blood flow [18].The arteriolar response to vasoactive substances can also
be altered during endothelial injury. The basal tone of arterioles is increased
in post ischemic kidneys as well as their reactivity to vasoconstrictive
agents. These arterioles also have decreased vasodilatory responses compared
with arterioles from normal kidneys. Alterations in local levels of
vasoconstrictors (angiotensin II, thromboxane A2, leukotrienes,
adenosine, endothelin-1) have been implicated in abnormal vascular tone [19].
Angiotensin II seems to play a key role by activating endothelin B or
prostaglandin H2-thromboxane A2 receptors. Systemic endothelin-1 levels increase with ischemia, and
administration of antiendothelin antibodies or endothelin receptor antagonists
has been reported to protect against ischemia-reperfusion injury [20].
Saralasin, an angiotensin II receptor antagonist, could also attenuate
angiotensin II vasoconstricting effect [21]. Nitric oxide, an
endothelial-derived relaxing factor, plays a theoretical protective role
against ischemic renal injury, by means of its vasodilatory effect and by decreasing
endothelin expression and secretion in the vascular endothelium. Of interest,
endothelial nitric oxide synthase is inhibited during endothelial injury [22].
A combination therapy consisting of
5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl
cysteine (NAC), drugs that inhibit the induction of proinflammatory cytokines
and nitric oxide synthase, and block tumor necrosis factor-alpha induced
apoptotic cell death,  has shown to attenuate
ischemia-reperfusion injury in a canine model of autologous renal
transplantation [23]. Early studies showed no conclusive evidence that
vasodilators (such as diltiazem or dopamine) or other compounds have any clinical
utility in either preventing or treating ischemic renal failure in humans thus
far [24–26]. More
recently, however, the highly selective dopamine type 1 agonist fenoldopam
mesylate [27] and the antianginal medication trimetazidine [28] appeared to aid
in restoring renal function to baseline values in patients with prolonged WI
time. Further research is needed.


## 3.1.2. Obstructive Mechanism

Normally, the cells are bathed in an extra cellular
solution high in sodium and low in potassium. This ratio is maintained by a
sodium pump (Na+-K + ATPase pump) which uses much of the adenosine triphosphate
(ATP) energy derived from oxidative phosphorylation. ATP is required for the
cellular sodium pump to maintain a high intracellular concentration of
potassium and a low concentration of sodium. The sodium pump effectively makes
Na+ an impermeant outside the cell that counteracts the colloidal osmotic
pressure derived from intracellular proteins and other anions [29].The ischemic insult causes a failure of oxidative
phosphorylation and ATP depletion, leading to malfunctioning of the sodium pump.
When the sodium pump is impaired, sodium chloride and water
passively diffuse into the cells, resulting in cellular swelling and the
“no-reflow” phenomenon after renal reperfusion. Cellular potassium and
magnesium are lost, calcium is gained, anaerobic glycolysis and acidosis occur,
and lysosomal enzymes are activated. This results in cell death. During
reperfusion, hypoxanthine, a product of ATP degradation, is oxidized to
xanthine with the formation of free radicals that cause further cell damage [29].
(See later.)As mentioned, the mechanism whereby ischemia and oxygen
depletion injure tubular cells starts with ATP depletion, which activates a
number of critical alterations in metabolism, causing cytoskeletal disruption
and loss of those properties that normally render the tubule cell monolayer
impermeable to certain components of filtrate. Cytoskeletal disruption causes
not only loss of brush-border microvilli and cell junctions but also
mislocation of integrins and the sodium pump from the basal surface to the
apical surface.In addition, impaired sodium reabsorption by injured
tubular epithelial cells increases the sodium concentration in the tubular
lumen. The increased intratubular sodium concentration polymerizes Tamm-Horsfall protein,
which is normally secreted by the loop of Henle, forming a gel and contributing
to cast formation. As a result, brush-border membranes and cells slough
obstruct tubules downstream. As mentioned before, these debris form casts that
obstruct tubules, and glomerular filtrate leaks from the tubular lumen across
denuded tubular walls into capillaries and the circulation (back-leak) causing
a reduction in the “effective” GFR. ATP depletion also activates harmful
proteases and phospholipases, which, with reperfusion, cause oxidant injury to
tubular cells, the so-called reperfusion injury [7].


## 3.1.3. Reperfusion Injury

WI insult followed by restoration of blood flow to the
ischemic tissue frequently results in a secondary reperfusion injury. Despite WI causing significant renal dysfunction,
reperfusion injury has been shown to be as damaging or even more detrimental
than renal ischemia itself, producing an inflammatory response that worsens
local kidney damage and leads to a systemic insult [30, 31].The reperfusion injury can be mediated by several
mechanisms including the generation of reactive oxygen species, cellular
derangement, microvessel congestion and compression, polimorphonuclear
(PMN)-mediated damage, and hypercoagulation. Reperfusion with the resulting
reintroduction of molecular oxygen of constricted microvessels leads to
congestion and red cell trapping. This vascular effect can reduce renal blood
flow by as much as 50% [32].During the reperfusion period, superoxide production in
the kidney is markedly enhanced by the transformation of xanthine dehydrogenase
to xanthine oxidase and the increase in free electrons in mitochondria,
prostaglandin H, and lipoxygenase with the coexistence of NAD(P)H  and
infiltrated neutrophils. Superoxide raises the following chain reactions,
producing hydroxyl radicals or other reactive oxygen species (ROSs), or interacts with nitric oxide (NO),
which is produced by macrophage inducible NO synthase, generating a highly
toxic radical peroxynitrite. These ROS and NO derived species consume tissue
antioxidants and decrease organ reducing activity [33].The exact magnitude of reperfusion injury is still
unclear. Some authors state that the role of free radicals mediated injury in
kidneys may not be as significant as in other organs given the low relative
activity of renal xanthine oxidase compared with the high endogenous activity
of superoxide dismutase [29].Notwithstanding, nicaraven
(N,N9-propylenebisnicotinamide), a drug that may actively trap free radicals
and prevent vascular constriction due to lipid peroxide [34] and edaravone
(3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186), a synthetic free radical
scavenger, have shown in vitro experiments to protect endothelial cells against
ischemic injury in different organs, including ischemically damaged kidneys
[35, 36]. Clinical studies are eagerly awaited.


## 4. For How Long Can the Kidney Tolerate Warm Ischemia?

Despite several animal studies
[37–39]  and clinical reports [40, 41] demonstrating kidney
tolerance to warm ischemia times beyond 30 minutes,  concern still remains regarding the potential for full-renal
function recovery after this time period [42]. The stoic 30-minute cutoff has
been questioned by some authors [43] on the grounds that kidneys harvested from
nonheart beating donors (NHBDs) have shown favorable recovery of renal function
in transplanted kidneys that sustained warm ischemia times well over 30 minutes
[44–46]. Nishikido et al. [45] found that the risk factors affecting
significant graft loss were WI time
more than 20 minutes, donor age above 50 years, and donor serum creatinine at
admission above 1.0 mg/dL. Today, most nonheart beating donor programs
currently exclude those donors with a WI time exceeding 40 minutes [45, 47–49].Although laparoscopic surgeons
are gaining further experience and are more ambitious to perform partial
nephrectomy for larger and deeper tumors, the 30-minute cutoff still remains
the accepted safe limit time beyond which irreversible kidney damage occurs in
the absence of renal cooling [50–52].Although early observations in dog models showed that
there may be substantial variation in kidney tolerance up to two or three hours
of ischemia [53] there is no doubt that the extent of renal damage after
transitory arterial occlusion exclusively depends on the duration of the
ischemic insult [25, 54, 55]. The literature also demonstrates that, even
within a tolerable period of WI, the longer the WI time the longer it takes for
the kidney to recover (or approach) its preoperative function [55]. Notwithstanding,
the maximum tolerable limit of renal warm ischemia time that can render
complete function recovery remains to be established in humans.The study by Ward [56] is commonly cited by opinion
leaders to state a maximum 30-minute tolerance of the kidney to WI. These
authors showed in dogs that warm ischemic intervals of up to 30 minutes can be
sustained with eventual full recovery of renal function. However, this study
was not strictly designed to establish the most accurate length of time a
kidney would be able to sustain reversible damage following ischemic injury.
What the authors actually concluded was that no additional protection to
ischemia could be gained by cooling below 15 degrees. Thus, they recommended 15 degrees as the
optimum temperature for use in clinical renal hypothermia.Research in rats, pigs, and monkeys has also been
conducted by other investigators. Laven et al. [38] found renal resilience to
WI beyond the traditionally accepted 30 minutes in a solitary kidney pig model.
Prolonged renal WI time increased the incidence of renal dysfunction during the
initial 72 hours after the ischemic insult. However, by 2 weeks after the WI
insult renal function returned to baseline in the 30, 60, and 90-minute WI
groups. However, the same study group found that prolonged WI time of 120
minutes produced significant loss of renal function and mortality [43].Martin et al. [57] proved potential kidney WI tolerability
of up to 35 minutes in a single kidney monkey model.Haisch et al. [58]
studies in dog models suggested that the window of reversible WI injury could
be as long as 2 hours after the insult.The question
remains whether findings in animal studies can be extrapolated to humans. One
limitation has to do with a reliable method to differentiate between
ischemic injury and the loss of renal volume secondary to tumor excision. The
ideal method to evaluate residual kidney function in the operated kidney is
still undefined. While most authors use serum creatinine assay or
99mtechnetium-labeled mercaptoacetyl triglycine (MAG3) renal scintigraphy with
split renal function, others, like Abukora et al. [59] proposed estimation of
parenchymal transit time (PTT) as a good
indicator of ischemic injury. Transit time is the time that a tracer remains
within the kidney or within a part of the kidney. However, the international
consensus committee on renal transit time, from the subcommittee of the
International Scientific Committee of Radionuclides in Nephrourology, recently
concluded that the value of delayed transit remains controversial, and the
committee recommended further research [60].Bhayani et al. [40] evaluated
118 patients, with
a single, unilateral, sporadic renal tumor, and normal contralateral kidney, who underwent
laparoscopic partial nephrectomy (LPN) to assess the effect of variable
durations of WI on long-term renal function. Patients were divided into 3
groups based on WI time: group 1, no renal occlusion (n = 42), group 2, WI <
30 minutes (n = 48), and group 3, WI > 30 minutes (n = 28). At a median followup
of 28 months (minimum followup of 6 months) median creatinine had not
statistically increased postoperatively and none of the 118 patients progressed
to renal insufficiency or required dialysis after LPN. The authors concluded
that WI time up to 55 minutes did not significantly influence long-term renal
function after LPN. A main limitation of this study has to do with the fact
that all patients had a normal contralateral kidney so that 6 months
postoperatively creatinine values could have reflected contralateral kidney
function.A similar study has been
conducted by Shekarriz et al. [61] on a substantially lower number of patients
(n = 17); however, the authors assessed kidney function using 99technetium
labeled diethylenetetraminepentaacetic acid scan renal scan with differential
function 1 month before and 3 months after surgery in all patients. The authors
found that all their patients preserved adequate renal function in the affected
kidney following temporary hilar clamping of up to 44 minutes. (The mean WI
time was 22.5 minutes.)In line with this author, Kane et al. [62] showed that
temporary arterial occlusion did not appear to affect short-term renal function
(mean followup: 130 days) in a series of laparoscopic partial nephrectomies
(LPNs) with a mean WI of 43 minutes (range: 25–65 minutes).Desai et al. [50] retrospectively assessed the effect of WI
on renal function after LPN for tumor, and evaluated the influence of various
risk factors on renal function in 179 patients under WI conditions. No kidney
was lost because of ischemic sequelae with clamping of the renal artery and
vein of up to 55 minutes. The mean WI time was 31 minutes. Nonetheless, the
authors concluded that advancing age and pre-existing azotaemia increased the
risk of renal dysfunction after LPN, especially when the warm ischemia exceeded
30 minutes.In contrast, Kondo et al. [63] found that patient age did
not influence residual function in patients undergoing partial nephrectomy,
while tumor size was the only significant factor that inversely correlated with
the relative 99technetium labeled dimercaptosuccinic acid (DMSA) uptake.Porpiglia et al. [52] assessed kidney damage in 18
patients 1 year after LPN with a WI time between 31 and 60 minutes. The authors
evaluated the contribution of the operated kidney to the overall renal function
by radionuclide scintigraphy with 99mTc-MAG3. They observed that there was an
initial significant drop of approximately 11% in the operated kidney’s
contribution to overall function, followed by a constant and progressive
recovery that never reached the preoperative value (42.8% at 1 year versus
48.3% before surgery). The authors stated by logistic regression analysis that
the loss of function of the operated kidney depended mostly on the WI time and
less importantly on the maximum thickness of resected healthy parenchyma.
Unfortunately, the full regression model that included 6 variables to predict
an event in only 18 patients is not shown in the manuscript.Recently, Thompson et al. [42] made
a retrospective review of 537 patients with solitary kidneys who underwent open
nephron sparing surgery by more than 20 different surgeons from both the Cleveland Clinic, Ohio,
USA, and Mayo Clinic, Minn, USA,
to evaluate the renal effects of vascular clamping in patients with
solitary kidneys. After adjusting for tumor
complexity and  tumor size, the author found in a subsequent analysis [64] that
patients with more than 20 minutes of WI were significantly more likely to have
acute renal failure (24% versus 6%, p 0.002) compared to those requiring less than 20
minutes, and this risk remained significant even after adjusting for tumor size
(odds ratio 3.4, p 0.025). Additionally, patients with more than 20 minutes of
WI were significantly more likely to progress to chronic renal failure (odds
ratio 2.9, p 0.008) and  were more than 4 times more likely to experience an
increase in creatinine postoperatively of greater than 0.5 mg/dL (odds ratio
4.3, p 0.001) compared to those requiring less than 20 minutes of WI. After
adjusting for tumor size, the risk of chronic renal failure (odds ratio 2.6, p
0.03) and an increase in creatinine of greater than 0.5 mg/dL (odds ratio 4.6,
p 0.002) remained statistically significant if more than 20 minutes of WI were needed. The authors
concluded that WI should be restricted to less than 20 minutes when technically
feasible, especially in patients with solitary kidneys.


## 5. What Are the Factors Affecting Tolerance to Warm Ischemia?

It often goes without saying that there may be individual
variation to WI tolerance. Baldwin et al. [37] observed that some of the 16
solitary porcine kidneys showed a rapid return to the dark red color, and other
animals demonstrated minimal color change during the several minutes following
complete hilar clamp removal, despite all of them receiving similar surgical
technique and ischemia time. Having acknowledged the potential for individual
variation, there may be other multiple factors that can affect tolerance to WI which
are herein described.It has been suggested that patients with solitary kidneys
might safely tolerate longer periods of ischemia than patients with both
kidneys as the result of development of a collateral vascular supply; [65–67] however, the
presence of vascular collateralization secondary to vascular occlusive
disease, [68] or yet other clinical entities like hypertension, [69] should warn
the surgeon for the possibility of a kidney less resistant to WI injury for the
likely presence of panvascular disease and or occult chronic renal
insufficiency.Another factor that
can impact ischemic damage is the method employed to achieve vascular control
of the kidney. When technically possible, depending on the size and location of
the tumor, it is helpful to leave the renal vein patent throughout the
operation. This measure has been proven to decrease intraoperative renal
ischemia and, by allowing venous backbleeding, facilitates hemostasis by
enabling identification of small, transected renal veins [1–3, 5].Animal studies have
shown that functional impairment is least when the renal arteryalone is occluded. Although some
authors found no difference [70] simultaneous occlusion of the renal artery and
vein for an equivalent time
interval is more damaging because it prevents, as mentioned, retrograde
perfusion of the kidney through the renal vein and may also produce venous
congestion of the kidney [2, 3, 71–73]. However, this benefit may not be observed in
patients undergoing LRP since the pressure of the pneumoperitoneum may
cause partial occlusion of the renal vein, thus, negating the advantage of
renal artery clamping only [72].Intermittent clamping of the renal artery with short periods of recirculation
may also be more damaging than continuous arterial occlusion, possibly because
of the release and trapping of damaging vasoconstrictor agents within the
kidney [39, 55, 71, 74–77].Manual (or instrumental) compression of the kidney parenchyma
to control intraoperative hemorrhage (as an alternative to clamping of the
pedicle) has the theoretical advantages of avoiding WI of the normal parenchyma
while allowing the surgeon to operate in an almost bloodless field, something
that could be particularly useful in peripherically located tumors. Although
animal studies have shown that the use of renal parenchyma compression may be
more deleterious than simple arterial occlusion [71, 76], this technique has
been recently “resuscitated” by some authors both in the open kidney surgery
[78–82] and in the
laparoscopic setting [83].When the surgeon
anticipates a WI time exceeding the “classical” 30 minutes, local renal hypothermia is used to protect
against ischemic renal injury. Hypothermia has been the most effective
and universally used means of protecting the kidney from the ischemic insult. Hypothermia reduces basal cell
metabolism, energy-dependent metabolic activity of the cortical cells, with a
resultant decrease in both the consumption of oxygen and ATP [84–86].There are multiple
ways of achieving hypothermia. Surrounding the fully mobilized kidney with
crushed ice (ice slush) is the most frequently used technique because of its
ease and simplicity [87, 88]. When using ice slush to reduce kidney
temperature, it is recommended to keep the entire kidney covered with ice for
10 to 15 minutes immediately after occluding the renal artery and before
commencing the resection of the tumor in order to allow core renal temperature
to decrease to approximately 20 degrees centigrade or less [2]. Mannitol, with
or without the addition of furosemide, should be administered intravenously 5
to 15 minutes before renal arterial
clamping as it increases renal plasma flow, decreases intrarenal
vascular resistance and intracellular edema, and promotes an osmotic diuresis
when renal circulation is restored [89]. Regular use of heparin to prevent intrarenal vascular thrombosis has not been
found to be useful [2, 3, 56].Other methods than the use of ice slush to achieve renal
hypothermia have also being explored, including application of ice-slurry [90, 91], antegrade perfusion of the
renal artery either via preoperative renal artery catheterization [92] or via
intraoperative renal artery cannulation [93], retrograde perfusion of the
collecting system with cold solutions [94, 95] or near-freezing saline irrigation
delivered with a standard irrigator aspirator [96] among others, some of them
particularly used in the laparoscopic setting. Very few studies compared kidney
cooling techniques; [97–100] however,
hypothermia by properly applying ice to the renal surface seems to be
equivalent to hypothermia by perfusion [98]. Perfusion of the kidney with a cold solution instilled via the renal
artery not only may have a theoretic
risk of tumor dissemination, but also requires participation of an
intervention radiology team to perform preoperative renal artery
catheterization, adding complexity and risks of potential complications to the
procedure [3]. On the contrary, continuous renal perfusion might have the
advantage of providing a more homogeneous and effective hypothermia for a more
extended period of time [99, 100]. It is generally accepted, founded on data
extrapolated from the kidney stone literature, that adequate hypothermia
provides up to 2 to 3 hours of renal protection from circulatory arrest [99, 101–104].Needless to say, generous preoperative and
intraoperative hydration, prevention of intraoperative hypotension, avoidance
of unnecessary manipulation or traction on the renal artery as well as the
aforementioned administration of mannitol are necessary to keep the kidney
adequately perfused before and after the ischemic insult.Ischemic preconditioning (IP) has emerged as a powerful
method of ameliorating ischemia/reperfusion injury not only the myocardium (as
initially described) [105] but also to other organs, including kidney. IP is a
physiologic phenomenon by which cells develop defense strategies to allow them
survive in a hypoxic environment. The original IP hypothesis stated that
multiple brief ischemic episodes applied to an organ would actually protect it
(originally the myocardium) during a subsequent sustained ischemic insult so
that, in effect, ischemia could be exploited to protect that organ (originally
the heart) from ischemic injury [105]. The “preconditioned” cells would become
more tolerant to ischemia by adjusting its energy balance to a new, lower
steady-state equilibrium. Specifically, preconditioned tissues exhibit reduced
energy requirements, altered energy metabolism, better electrolyte homeostasis
and genetic reorganization, giving rise to the concept of “ischemia tolerance.”
IP also induces “reperfusion tolerance” with less reactive oxygen species and
activated neutrophils released, reduced apoptosis and better microcirculatory
perfusion compared to not preconditioned tissue. Systemic  reperfusion injury is
also diminished by preconditioning [31]. A review by Pasupathy and Homer-Vanniasinkam [31]
showed that IP utilizes endogenous mechanisms in skeletal muscle, liver, lung,
kidney, intestine, and brain in animal models to convey varying degrees of protection
from reperfusion injury. To date, there are few human studies, but some reports
suggest that human liver, lung, and skeletal muscle acquire similar protection
after IP. IP is ubiquitous but more research is required to fully translate
these findings to the clinical arena.Some authors propose that during
laparoscopy, the increase of intra-abdominal pressure due to the
pneumoperitoneum may create an IP-like situation that might increase kidney
tolerance to subsequent WI and reduce tissue injury [106–110]. For this reason, it might theoretically be possible to
increase WI time during LPN, compared to open surgery, something which is still
very far from being demonstrated [30, 109–111].In contrast, other studies expressed some concern about
the potential harm of pneumoperitoneum and increased intra-abdominal pressure
(IAP) on kidney function. Several experimental animal studies have investigated
the effect of pneumoperitoneum on renal function. While some authors
demonstrated that increased IAP by insufflation of CO2 gas resulted in
decreased renal blood flow that may lead to ischemia and subsequent decreased
glomerular filtration rate [112], others denied such effect [37, 113].Kirsch et al. [112] showed a decrease in
urine output and GFR with increasing IAP. A pneumoperitoneum of 15 mmHg for 4 hours
resulted in a decrease in renal blood flow to 70% of baseline. Even IAPs of 4
and 10 mmHg resulted in a reduction of the renal circulation of 34% and 41%,
respectively. Although, the decreased urinary output during prolonged IAP
greater than or equal to 15 mmHg in the animal model was associated with a
corresponding decrease in renal vein flow, it did not appear to be associated
with any permanent renal derangement nor any transient histological changes [114].
After the release of the pneumoperitoneum or pneumoretroperitoneum, the renal
function and urine output return to normal with no long-term sequelae, even in
patients with pre-existing renal disease [115].Lind et al. [113] found that WI time of 20 minutes did not
impair graft function and histomorphology during 1 year of followup after renal
transplantation in a syngeneic rat model. Most important, WI in combination
with pneumoperitoneum did not result in an additive negative effect on
long-term graft function.In addition, Baldwin et al. [37] observed that temporary
serum creatinine elevation evident after 60 and 90 minutes of ischemia
normalized within 7 days in 16 farm pigs which had been nephrectomized 14 days
prior to the laparoscopically applied ischemic insult. No difference from the
controls was noted in those pigs receiving 30 minutes of ischemia during the
laparoscopic procedure. Of note, insufflation had been maintained for 150
minutes at 15 mmHg in all animals. Those findings suggested that in
laparoscopic renal surgery, WI times of up to 90 minutes (and a pneumoperitoneum
of up to 150 minutes) might be well tolerated and followed by complete renal
recovery. The reader is referred to the excellent review by Dunn and McDougall [115]
for further information on the impact of pneumoperitoneum
on renal physiology.


## 6. Conclusions

The maximal duration of WI allowable before the onset of
irreversible renal damage continues to be a topic of debate, irrespective of
the surgical approach. In addition, there seems to be variation among patients,
possibly related to surgical technique, patient age, presence of collateral
vascularization, and indemnity of the arterial bed, among others.
Unfortunately, no method exists for predicting preoperatively or intraoperative
monitoring for renal injury. Surgeons should  exert extreme efforts to keep warm
ischemia time as short as possible. When WI time is expected to exceed from 20 to 30
minutes, specially in patients whose baseline medical characteristics put them
at potentially higher, though unproven, risks of ischemic damage, the
time-tested way around this time limit has been renal hypothermia, regardless
of what the time limit may exactly be.



---

*Source: 102461-2008-07-15.xml*