Cytotoxic
Effects of Contrast Media on Renal Tubular Cells. Pathogenesis of
Contrast-induced
Acute
Kidney Injury and Prevention
Michele
Andreucci, Teresa Faga, Ashour Michael
Michele
Andreucci, Teresa Faga, Ashour Michael,
Nephrology Unit,
Department of Health Sciences, Campus Salvatore Venuta, Magna Graecia
University, Viale Europa, loc. Germaneto, I-88100 Catanzaro, Italy
Correspondence to: Michele Andreucci, MD, PhD, Associate
Professor of Nephrology, Magna Graecia University, I-88100 Catanzaro, Italy
Email: andreucci@unicz.it
Telephone: +39-339-6814750
Received: January 8,
2015
Revised: January 30, 2015
Accepted: February 4, 2015
Published online: March 30, 2015
ABSTRACT
The continued
growth in radiographic procedures for diagnostic or therapeutic purposes is
leading to an increasing number of cases of contrast-induced Acute Kidney
Injury (CI-AKI) secondary to Iodinated RadioContrast Agents (IRCA). In this
review, following a brief description of IRCA and CI-AKI, the pathogenesis of
CI-AKI is discussed in detail, particularly focusing on the direct toxic
effects by IRCA on endothelial cells, red blood cells and mainly on renal tubular
epithelial cells. In vitro studies of the effects of different IRCA on
various signalling pathways known to play a role in cellular survival, growth
and proliferation are reported, demonstrating that IRCA cause several and
significant changes in a variety of cell signalling molecules that play
important roles in cellular homeostasis. Factors favouring toxic effects by
IRCA on renal tubular epithelial cells and protection of tubular cells against
IRCA toxicity (by e.g. asialoerythropoietin, human serum albuminCThioredoxin,
extracellular volume expansion) are discussed. Measures to prevent IRCA
nephrotoxicity by antioxidants and recent studies demonstrating reversal of
IRCA toxicity on human renal proximal tubular cells by white grape juice
extract conclude the review.
© 2015 ACT. All
rights reserved.
Key words: Contrast induced nephropathy; Nephrotoxicity; Cell
death, Kinase; Cell signalling
Andreucci M, Faga
T, Michael A. Cytotoxic Effects of Contrast Media on Renal Tubular Cells. Pathogenesis
of Contrast-induced Acute Kidney Injury and Prevention. Journal of
Biochemistry and Molecular Biology Research 2015; 1(1): 1-13 Available from: URL:
http://www.ghrnet.org/index.php/jbmbr/article/view/1012
INTRODUCTION
The continued growth in radiographic procedures for either diagnostic
or therapeutic purposes (coronary angiography and percutaneous coronary
interventions) is leading to an increasing number of cases of contrast-induced
Acute Kidney Injury (CI-AKI) secondary to Iodinated RadioContrast Agents (IRCA)[1-3].
This is in part due to the type of patients undergoing these procedures,
usually being of advanced age, with one or more comorbid conditions, such as
advanced vascular disease, severe long-standing hypertension, diabetes and some
renal function impairment[4-7].
The
Iodinated RadioContrast Agents (IRCA)
In the last few decades, attempts have been made by many investigators
to reduce the nephrotoxicity of IRCA making them more soluble, while at the
same time allowing more opacity by increasing the content of iodine atoms per
molecule. Thus, IRCA have undergone a series of chemical modifications.
Firstly, hydrogen atoms on the benzene ring have been substituted in order to
reduce protein binding: acetrizoates and diatrizoates were obtained in this
way. These compounds are ionic and are known as high-osmolar contrast media.
The next step was to replace the carboxyl groups with non-polar groups giving
non-ionic soluble molecules with lower osmolality (low-osmolar contrast media);
these were further improved by the addition of more hydroxyl groups for
increased hydrophilicity, followed by a more even distribution of the hydroxyl
groups on the molecule. Finally, the dimerization of two molecules via side
chains on the benzene ring resulted in the non-ionic and iso-osmolar group of
contrast media with increased iodine atoms per molecule[8,9]. Thus,
these chemical modifications have resulted in the availability of newer
low-osmolar and iso-osmolar IRCA immediately used in clinical practice, and it
is acknowledged that the low-osmolar IRCA and iso-osmolar IRCA are less
nephrotoxic than high-osmolar IRCA[10]. Despite this, in vitro
cell culture studies have suggested that all of these types of IRCA still have
a direct toxic effects on many different types of cells and may cause CI-AKI.
Modern IRCA are based on the triiodinated benzene ring[9]. The most
common IRCA used in clinical practice are listed in table 1[11,12].
Contrast-Induced Acute Kidney
Injury (CI-AKI)
The most important adverse effect of IRCA is undoubtedly CI-AKI,
frequently called Contrast-Induced Nephropathy (CIN). It is an asymptomatic
transient impairment of renal function, usually non-oliguric, occurring 24-72
hours after exposure to intravascular injection of IRCA that cannot be
attributed to other causes[13-15]. The KDIGO Group[16]
proposes that the term Contrast Induced-Acute Kidney Injury (CI-AKI) (rather
than CIN) be used for patients developing AKI secondary to intravascular
radiocontrast media exposure.
The decline of
renal function is mirrored by the rise in serum Creatinine (SCr) that reaches
its peak on the third to fifth day after the injection of IRCA and returns to
baseline within 10-14 days[17]. The extent of the rise in SCr for
defining CI-AKI following the intravascular injection of IRCA is an increase in
either its absolute value (by 0.5 mg/dL or greater) or its relative value (by
25% or greater on the baseline value). CI-AKI may also be defined as a decrease
(to 30-60 mL/min/1.73m2 - renal insufficiency-or less) in the
estimated glomerular filtration rate (eGFR), i.e. the creatinine clearance
calculated by using either the MDRD (Modification of Diet in Renal Disease)
calculation[18] or the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
equation[19], or the very simple Cockcroft-Gault formula[20].
Some Authors
have suggested that an evaluation of renal function by serum Cystatin C (or the
CKD-EPI cystatin C equation) is better than SCr. Undoubtedly, since the
relationship between SCr and GFR is exponential, small SCr differences will
greatly impact the GFR values at low SCr values (corresponding to high GFR
values), but the same difference will have minimal impact at high SCr values
(corresponding to low GFR values)[21]. Therefore, to detect the
early impairment of renal function due to nephrotoxic radiographic contrast
media, it is important to have a marker which is sensitive to small changes of
GFR when GFR is high. It has been thought that estimates of small changes of
renal function based on a rise in serum cystatin C to be more accurate than
those based on a rise in SCr when the GFR is near to the normal range. Thus,
the behaviour of SCr has been compared to that of cystatin C, although
unfortunately, it has turned out that the relationship between serum cystatin C
and GFR was also exponential[22]. Equations based on standardized
cystatin C (CKD-EPI cystatin C equation) or cystatin C and creatinine (combined
CKD-EPI equation) were then proposed by the CKD-EPI consortium in 2012[23].
The better suitability of these equations (and especially the combined CKD-EPI
equation) has been shown in different populations[24-26]. It has
been recently observed that eGFRcr-cys, but not eGFRcys, is more accurate than
eGFRcr in measuring small changes in renal function[27]. Even the
recent KIDGO guidelines on CKD[28] recommended using eGFRcr for the
initial evaluation and using eGFRcys or eGFRcr-cys for confirmation in the
clinical settings in which eGFRcr is less accurate. But other Authors[29,30]
found that estimates of GFR based on cystatin C were not superior to those
based on SCr in the general population. In other words, there is no evidence
that equations based on cystatin C alone or in combination with creatinine
provide better GFR estimates in middle-aged members of the general population
than the commonly used MDRD and CKD-EPI equations.
Sometimes
CI-AKI may cause a severe impairment of renal function with oliguria (<400
mL/24 hrs), requiring dialysis. In such circumstances, according to the KDIGO
Group[16], it is reasonable to talk of Acute Renal Failure (ARF). In
these cases the mortality is high. The clinical feature and the management of
ARF caused by IRCA are the same as that for ARF due to other causes[31-37].
CI-AKI is
uncommon in patients with normal pre-existing renal function. It occurs more
frequently in patients with renal impairment, particularly if associated with
diabetes mellitus[38].
Pathogenesis
of Contrast-Induced Acute Kidney Injury (CI-AKI)
The pathogenesis of Acute Kidney Injury (AKI) secondary to Iodinated
RadioContrast Agents (IRCA) is not fully understood. Many factors are involved
(Figure 1):
(1)
Hemodynamic changes: after intravascular injection, IRCA cause immediate and
transient vasodilatation followed by prolonged vasoconstriction, leading to
renal ischemia, especially in the outer renal medulla; the consequence will be
a decrease of Renal Blood Flow (RBF), thereby leading to a decrease in the GFR[13,39].
(2) Renal
medullary hypoxia: resulting from (a) the vasoconstriction of vasa recta[40,41],
(b) changes in erythrocyte membrane
skeleton[40] (see later), (c) increase in tubular reabsorption in
the thick ascending limb of Henles loops (see later).
(3) Tubular
obstruction due to the increase in intratubular pressure due to the increased
viscosity of the renal tubular fluid, thereby contributing to the decrease in
the GFR[39].
(4) Formation
of reactive oxygen species (ROS)[42-44], caused both directly by
IRCA and by renal medullary hypoxia; they are responsible for (a) endothelial
and tubular epithelial cell damage, (b) increase of renal parenchymal hypoxia
by virtue of endothelial dysfunction and dysregulation of tubular transport[45,46]
(c) decrease of NO synthesis that is believed to be due to its reaction with
ROS, in particular superoxide anions (O2.-)[47,48],
leading to the formation of the more powerful oxidant detrimental peroxynitrite
anion (ONOO-)[49].
(5) Direct
cytotoxicity, which has been suggested to be due, at least in part, to the free
iodine present in solutions of IRCA that may lead to apoptosis and cell death
of both endothelial and tubular cells[47].
Many in
vitro studies have investigated the toxicity of IRCA using different types
of cultured cells: renal epithelial cells, mesangial cells, endothelial cells,
smooth muscle cells, hepatic cells, human fibroblasts, pulmonary mast cells,
human embryonic kidney cells and human neutrophils.
Direct
toxic effects by IRCA on endothelial cells
All IRCA exhibit a more or less strong effect on endothelial cells[50-53].
The
endothelial cells are the first to come in contact with intravascular-injected
IRCA. The endothelial damage, represented by nuclear protrusion, cell
shrinkage, fenestration of the endothelial layer and formation of microvilli
(blebbing) on the cell membrane, and cellular apoptosis have been observed by
scanning electron microscopy[54]. The damaged endothelial cell (a)
may contribute to the decrease in NO in the vasa recta[47] and (b)
may release endothelin that causes vasoconstriction (Figure 1). Heyman et al[55]
have, in fact, demonstrated that the i.v. administration of contrast media in
rats induced an increase in plasma concentration of endothelin; furthermore,
contrast media stimulated endothelin release from cultured bovine endothelial
cells. These results suggest a direct effect of ionic and nonionic contrast
agents on vascular endothelium to release endothelin[39].
Direct
toxic effects by IRCA on red blood cells
IRCA exhibit a toxic effect also on erythrocytes[56-63].
Human
erythrocytes circulating in the body are normally biconcave discocytes. Their
excess surface area and the elasticity of their membranes provide them with the
flexibility needed to pass through very small capillaries, demonstrating an
ability for repeated large deformation[64].
The
erythrocyte membrane consists of a phospholipid bilayer with embedded membrane
proteins and is associated on the cytoplasmatic side with a network of
proteins, the membrane cytoskeleton[65]. The bicarbonate/chloride
exchanger band3 is the most abundant protein in the erythrocyte membrane[66].
It has a very important role in gas exchange, senescence and removal of cells
from the circulation, and functions as a point of attachment for the
cytoskeleton, maintaining the mechanical and osmotic properties of the
erythrocyte, i.e. membrane stability and flexibility[67,68]. An
intact cytoskeleton is vital for normal cell shape.
Under the
influence of various agents, human erythrocytes change their shapes from the
discocytes to stomatocytes or echinocytes[69]. Some radiographic
agents induce shape changes from discocytic to echinocytic cells[56,60,70].
The echinocyte formation is associated with a rigidification of the cells
bearing the risk of a hindered capillary passage of the echinocytes[64],
thereby contributing to the outer renal medullary hypoxia (Figure 1).
It has been
demonstrated that the incubation of erythrocytes in plasma supplemented with
the IRCA iopromide 370 induced rounded bubble-like protrusions from their cell
membrane containing almost completely long bundles of actin fibres[64].
Two classes of
IRCA, having different iodine concentrations, were examined for their effects
on erythrocytes: Iodixanol (having an iodine concentration of 320 mg Iodine/mL)
and Iopromide (370 mg Iodine/mL). Both IRCA provoked echinocyte formations
accompanied by a reorganization of band3 and/or spectrin filaments with
exocytosis of particles. The study revealed changes in shape and aggregation of
erythrocytes in contact with IRCA that coincided with changes in the structure
of the membrane skeleton. Iopromide induced markedly more severe alterations of
the membrane skeleton compared to iodixanol[64].
The formation
of echinocytes and stomatocytes observed upon incubation of erythrocytes with IRCA
may have a negative effect on the rheology of the blood[47], thereby
impairing renal perfusion with increase of outer renal medullary ischemia
(Figure 1).
Direct
toxic effects by IRCA on renal tubular epithelial cells
Thus, as we have mentioned, in the pathogenesis of CI-AKI a direct
toxic effects by IRCA on renal tubular epithelial cells are believed to play an
important role in causing Contrast-Induced AKI (CI-AKI)[71,72]
(Figure 1).
Once filtered
by the glomeruli, IRCA are concentrated in the renal tubules, as a result of
water and salt reabsorption by the proximal tubules, and are able to cause
direct injury to the renal tubular cells. The consequent damage has been
observed in isolated tubular segments and in cultured cells substantiated by disruption
of cell integrity and apoptosis, that may be aggravated by factors, such as
tissue hypoperfusion and hypoxia caused by IRCA and by clinically unfavourable
conditions, such as pre-existing renal impairment, particularly if associated
to diabetes, salt depletion, congestive heart failure and concurrent use of
nephrotoxic drugs[47,73-78].
In vitro
cell culture studies have shown that important cell signalling pathways are
affected by IRCA. These pathways may determine cell fate, such as death, survival,
proliferation, release of hormone, and may be triggered by mechanical,
chemical, light and thermal stimuli, and it is feasible that these signaling
pathways are involved in renal injury and repair following the administration
of IRCA[9].
Characterization
of some of these intracellular pathways in cells exposed in vitro to
IRCA may shed some light on the mechanisms of toxicity of the IRCA and possibly
help in future development of pharmacological therapies in order to reduce the
risk of CI-AKI[79].
Kinase-mediated intracellular signalling pathways can modulate cell
growth, proliferation, death and inflammation[80-83]. By knowing
these pathways it may be possible to block a cell death pathway, thereby
modifying the extent of injury and preventing renal necrosis[84].
For example,
the pro-survival and pro-proliferative kinases Akt and ERK1/2 have been shown
to be dephosphorylated (deactivated) whilst pro-inflammatory/cell death
molecules, such as the p38 and JNK kinases and the transcription factor NF-kB
may be activated by IRCA, accompanied by activation of apoptotic mediators such
as caspases[9].
The most
important and useful cells used for evaluating the nephrotoxicity of IRCA are
the immortalized human proximal tubular cell line, named HK-2, which retains
the phenotypic expression and functional characteristic of human proximal
tubular cells, as described by others[85-87].
Cellular
signalling pathways affected by IRCA
Our in vitro studies have demonstrated the effects of different
IRCA on various signalling pathways known to play a role in cellular survival,
growth and proliferation. The incubation of human renal proximal tubular
epithelial cells (HK-2 cells) with IRCA (diatrizoate, iopromide or iomeprol),
in fact, caused a dramatic dephosphorylation (deactivation) of Akt, a kinase
known to play a role in cell survival[81]. This was accompanied by
effects on downstream targets of Akt, such as p70S6 kinase (inactivated) which
is involved in protein synthesis and the FOXO (Forkhead) family of
transcription factors (dephosphorylated and hence activated)[88].
Both diatrizoate and iopromide caused a decrease in HK-2 cell viability, as
determined by the chemical reduction of MTT
[3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide[89]],
which was partially alleviated by the transfection with plasmids encoding the
constitutively-active Akt[88]. Transfection of HK-2 cells with
plasmids encoding the constitutively active form of Akt only partially
recovered cell viability. Diatrizoate also caused a dephosphorylation of mTOR
and ERK1/2, kinases known to play an important role in cell proliferation and
survival[90], which was greater with respect to iopromide, iomerol
or iodixanol[79,88]. Western blot analysis of whole lysates prepared
from kidneys removed from rats treated with the IRCA iomeprol and the IRCA
iodixanol also showed lowered levels of phospho-Akt and phosho-ERK1/2 compared
with lysates obtained from control non-treated rats[79].
We have also
demonstrated in HK-2 cells that the high osmolar diatrizoate also caused a
greater activation of the c-Jun N-terminal and p38 mitogen activated protein
kinases (JNKs and p38 MAPKs respectively) together with a corresponding
increase in the pro-inflammatory cytokine IL-8[91-93] compared with
low osmolar iomeprol at the same concentration of iodine[94].
Incubation of
HK-2 cells with high osmolar diatrizoate, low osmolar iomeprol or iso osmolar
iodixanol at concentrations of 75 and 100 mg Iodine/mL for up to 3 h did not
result in caspase-3 cleavage[79]. However, in HK-2 cells that had
been previously exposed to diatrizoate for 2-3 h and then incubated for a
further 22 h (after removal of the IRCA), evidence for caspase-3 cleavage was
observed[79,94].
Since the use
of large doses of IRCA represent risk for CI-AKI that is dose-dependent, these
studies were carried out using IRCA doses of 75 mg Iodine/mL, based on the
dosage commonly used in clinical practice of 1.5-2.5 mg Iodine/kg b.w., leading
to plasma concentrations of 15-20 mg Iodine/ml. Since, in the kidney, 70-80% of
the ultrafiltrate is re-absorbed in the proximal convoluted tubule, the IRCA
concentration will therefore range between 75-100 mg/mL[74,79].
Difference
between low osmolar iomeprol and iso osmolar iodixanol
We have also studied the different effects of the IRCA iomeprol,
iodixanol and sodium diatrizoate on renal cell cultures. Our cell viability
studies indicate that iodixanol is toxic to HK-2 cells, but less so than
iomeprol. Iomeprol, in fact, caused a greater decrease in phospho-Akt (at Ser
473) than iodixanol and this was dependent on the concentration of the IRCA
which have been used.
As mentioned
above, cell viability was measured by the ability of viable cells to reduce MTT[89].
HK-2 cells were grown to a confluence of approximately 90%, and incubated for
18-20 hours in serum-free medium prior to experimentation. For experiments,
cells were incubated for 2 hours with the IRCA; then the IRCA was removed by
replacing the culture medium with fresh serum-free medium. Whilst both IRCA
caused a significant decrease in cell survival with respect to control
(non-treated) cells (p<0.001), diatrizoate (32% decrease in cell
viability) had a significantly greater effect than iomeprol (20% decrease in
cell viability) (p<0.001).
Thus, we have
demonstrated with diatrizoate a significantly greater phosphorylation (i.e.
activation), of signalling molecules that are known to be involved in cell
death, namely the JNK and p38 MAP kinases subfamilies[82,95,96] than
with iomeprol[94]. Furthermore, the viability of these cells have
been assessed after removal of the IRCA stress for up to 22 h, meanwhile
determining which signalling molecules, involved in cell death/survival, are
activated/deactivated. Considering the proposed role of these molecules in cell
death and apoptosis[82,95,96], the activation of these molecules by
IRCA may have also contributed to the decrease in cell viability.
Other studies
have also supported our findings in suggesting that the JNK and p38 MAP kinases
may be involved in IRCA-induced apoptosis in HEK293T cells and in LLC-PK1 cells
respectively[97,98].
In conclusion,
in vitro cell culture studies have demonstrated that IRCA cause several
and significant changes in a variety of cell signalling molecules that play
important roles in cellular homeostasis, including the deactivation of
molecules such as Akt and ERK1/2 that enable cells to survive stress and to
proliferate as well as to regulate the synthesis of vasoactive molecules.
Furthermore, other molecular species are increased or activated: that may be
detrimental; reactive oxygen species and signalling molecules such as the p38
and JNK kinases and transcription factors such as NF-kB that may mediate cell
death and inflammation[9].
Factors
favouring toxic effects by IRCA on renal tubular epithelial cells
Salt depletion (frequently indicated with the term dehydration) will
favour the toxic effects of IRCA through several mechanisms:
(a) by
increasing the direct toxic action of IRCA on renal tubular epithelial cells;
salt depletion causes proximal tubular over-reabsorption that will make IRCA
more concentrated within the tubular lumen meanwhile reducing the flow rate of
tubular fluid, consequently increasing the contact time between IRCA and
tubular epithelial cells. Thus, salt depletion will increase the toxic effect
of IRCA on renal tubular epithelial cells.
(b) by
increasing the renal vasoconstriction with reduction of RBF. Such
vasoconstriction is particularly important in the outer renal medulla because
of its peculiar anatomical reasons. The outer renal medulla, in fact, even
under normal physiological conditions, receives a little amount of blood
because of its distance from the descending vasa recta. This
hypoperfusion leads to little local oxygen (O2) delivery despite the
high local O2 consumption due to the important active tubular
reabsorption in S3 segments of proximal renal tubules and in the medullary
thick ascending limb of the Henles loops that are located there. Salt
depletion and the consequent vasoconstriction will aggravate the discrepancy
between low O2 delivery and the O2 requirement. Thus, the
outer renal medullary hypoxia, a crucial point in the pathogenesis of CI-AKI
(Figure 1), is made worse by salt depletion[99].
Obviously, vasoconstrictive agents, such as adenosine and endothelins,
by increasing vasoconstriction, particularly in the outher renal medulla, will
aggravate outer renal medullary hypoxia. The renal vasculature in patients with
diabetes mellitus has a higher sensitivity to adenosine, a vasoconstrictive
agent. Since IRCA increase the release of renal adenosine, and stimulate renal
adenosine receptors, this may in part explain the particular susceptibility of
diabetic patients to IRCA[14,100]. The administration of IRCA to
diabetics acutely reduces renal parenchymal oxygenation through the increased
production of vasoconstrictive endothelins, a reduction that is most prominent
in the renal medulla, since it already functions at low oxygen tension[101].
Since diabetics already have increased circulating and renal endothelin levels,
this also may in part explain the particular susceptibility of diabetic
patients to IRCA[14].
Outer renal
medullary hypoxia leads to the formation of reactive oxygen species (ROS)[42,43]
that may exert direct tubular and vascular endothelial injury and might further
intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and
dysregulation of tubular transport[45,46] (Figure 1).
The decrease
in Nitric Oxide (NO) may be due to its reaction with ROS, in particular with
superoxide anions (O2.-)[47,48].
This reaction may lead to the formation of the more powerful oxidant
peroxynitrite anion (ONOO-)[49] that may be more
detrimental to the endothelial cells. Hence, the reaction of the ROS with NO
not only causes a reduction in the levels of the vasodilator NO, but also leads
to the formation of a potent oxidant that exacerbates cell injury[102]
(Figure 1).
Patients with
chronic renal failure (CRF) have defective antioxidant systems[103]
and increased oxidative stress associated with inflammation and endothelial
dysfunction[104]. This may explain why pre-existing renal failure
represents the most common condition predisposing to the development of CI-AKI[39].
Concomitant
use of potentially nephrotoxic drugs, such as aminoglycosides, vancomycin,
amphotericin B, dipyridamole, metformin and nonsteroidal anti-inflammatory
drugs will potentiate the toxicity of IRCA on epithelial cells[40,105].
Undoubtedly,
the toxicity is different for different IRCA. Thus, at equal iodine
concentrations (e.g. 300 mg Iodine/mL) high osmolar IRCA have greater cytotoxic
effects on proximal tubular cells in vitro than do low or iso osmolar
IRCA[73]. IRCA cytotoxicity has been suggested to be due, at least
in part, to the free iodine present in solutions of IRCA and that leads to
apoptosis and cell death of both endothelial and tubular cells[47].
It is important to choose the least nephrotoxic radiocontrast agent: the
iso-osmolar iodixanol and the low-osmolar iopamidol appear, in fact, to be the
IRCA of first choice to reduce the risk of CI-AKI[106] and to use
them with the lowest dosage possible.
Intracellular
Ca2+ overload induced by IRCA
Under physiological conditions, the Na+/Ca2+
exchanger (NCX) can pump the Ca2+ outside the renal tubular
epithelial cells using the Na+ concentration gradient across the
cell membrane to keep a low intracellular Ca2+ level. After IRCA
injection, NCX may reversely extrude Na+ for Ca2+ influx
and result in intracellular Ca2+ overload that is considered to be
an important factor in the pathogenesis of CI-AKI[107,108] (Figure
1). The increase in intracellular calcium, in fact, provokes a vasoconstrictive
response in intrarenal circulation and would be an important mediator of
epithelial cell apoptosis and necrosis. On this basis, Calcium Channel Blockers
have been hypothesized to have protective effects against CI-AKI. But their use
has given controversial results, sometimes protective and sometimes with no
benefit at all[105].
Protection
of epithelial tubular cells against IRCA toxicity by asialoerythropoietin
Erythropoietin (EPO), the cytokine widely used for the treatment of
anemia in patients with CRF, has been found to interact with its receptors,
expressed in a great variety of nonhematopoietic cell types: neurons,
endothelial cells, vascular smooth muscle cells, cardiomyocytes, mesangial
cells, renal proximal tubular cells. On these cells EPO induces a cytoprotective
cellular response: mitogenesis, angiogenesis, promotion of vascular repair and
inhibition of apoptosis, independent of EPOs effects on erythropoiesis[109].
Thus, EPO has been demonstrated to protect the kidney in experimental animals
against the injury and dysfunction caused by ischemia-reperfusion[110,111]
and to enhance recovery after cisplatin-induced acute renal failure in the rat[112].
But it has also been able to attenuate IRCA-induced ARF in rats[113].
Desialylated EPO (asialoEPO), is an EPO derivative that has EPO receptorC
binding affinity similar to native EPO; it has been reported to retain
neuroprotective activities. It has been hypothesized that asialoEPO could also
attenuate renal injury in experimental ARF. Thus, both EPO and a nonhematopoietic
EPO derivative, asialoEPO, have been recently demonstrated to prevent the
development of renal dysfunction as assessed by biochemical parameters in a rat
model of CI-AKI. It has also been demonstrated that either EPO or asialoEPO
markedly suppressed renal tubular injuries as assessed by histologic
examination when administered as a single intravenous bolus injection 1 h
before the injection of contrast medium. In conclusion, both can directly
prevent the contrast medium-induced apoptosis of renal tubular cells observed
both in vivo and in vitro[109].
Protection
of epithelial tubular cells against IRCA toxicity by human serum albuminCThioredoxin
(HSACTrx)
Thioredoxin-1 (Trx) is a ubiquitous low-molecular-weight protein,
produced in the human body in response to oxidative stress conditions, with
protective effect against oxidative stress being ROS scavenger. A human serum
albuminCthioredoxin fusion protein (HSA-Trx) has recently been obtained with a
half-life 10 times longer than that of thioredoxin. In vivo (in rats)
and in vitro (on human proximal tubular cells) studies have demonstrated
its ROS scavenging activity. HSA-Trx prevented
CI-AKI and renal tubular apoptosis, via its extended antioxidative action, in a
rat model of ioversol-induced CI-AKI[12,114].
The
protective effects of extracellular volume expansion
Consistent with the increasing effect of salt depletion on toxicity by
IRCA, the extracellular volume expansion has a protective effect. The expansion
of intravascular volume, in fact, will suppress renin-angiotensin cascade and
consequently will reduce renal vasoconstriction and hypoperfusion. Furthermore,
the resulting increase in urine output, because of reduction of proximal
tubular reabsorption (caused by volume expansion), will limit the duration of
IRCA contact with renal tubules and consequently their toxicity on tubular
epithelium[99,115,116]. In clinical practice adequate protection is
obtained with i.v. infusion of 0.9% saline at a rate of approximately 1 mL/kg
b.w. per hour, beginning 6-12 hours before and continuing for up to 12-24 hours
after the radiographic examination (if urine output is appropriate and
cardiovascular conditions allow it)[20,117]. Some Authors suggest
using sodium bicarbonate hydration that has been shown to be superior to sodium
chloride in some clinical studies and meta-analysis[118-128]. It is
believed that the use of bicarbonate causes the alkalinization of tubular fluid
leading to a reduction in the production and the neutralization of oxygen free
radicals, thereby protecting the kidney from injury[121,122,129,130].
For coronary angiography or intervention, 154-mEq/L infusion of sodium
bicarbonate as a bolus of 3 mL/kg b.w./hour for 1 hour before the
administration of IRCA, followed by 1 mL/kg/hour for 6 hours during and after
the procedure, have been used[119]. Unfortunately, other studies
have not found any benefit with sodium bicarbonate hydration versus sodium
chloride[131-134] or have even observed an increased incidence of
CI-AKI[135].
Protection
of tubular damage by steroids
In the last few years, several studies investigated the significance
and clinical utility of new biomarkers of kidney damage. In addition to
biomarkers representing changes in renal function (e.g., serum creatinine or
cystatin C), those biomarkers reflecting kidney damage also seem to be
important: kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated
lipocalin (NGAL). These may be present even when renal function has not been
impaired as yet, thereby identifying a new category of patients, those with
subclinical AKI. KIM-1 is a transmembrane protein not expressed in normal
kidney but upregulated in dedifferentiated proximal tubule cells after ischemic
or nephrotoxic AKI. KIM-1 was elevated in patients with ischemic acute tubular
necrosis, but increased urinary levels of KIM-1 have been reported also in
patients with CI-AKI[136]. The biomarker most investigated in CI-AKI
is NGAL. NGAL is a ubiquitous 25 KDa protein, covalently bound to gelatinase
from human neutrophils, and is a marker of renal tubular injury. Serum NGAL
(sNGAL) and/or urine NGAL (uNGAL) levels have been shown to predict AKI in
ischemic kidney injury, including CI-AKI[136].
It has been
suggested that oral prednisone given concurrently with i.v. saline may protect
renal tubules against the toxicity of IRCA[137]. This is based on
the fact that steroids may have a favourable impact on inflammation and renal
tubular cell apoptosis and necrosis, as observed in models of renal
ischemia-reperfusion in which dexamethasone had a protective effect against
injury. In rats with renal ischemia-reperfusion injury, a single dose of dexamethasone
administered before ischemia, or at the onset of reperfusion, in fact,
ameliorated biochemical and histologic acute kidney injury after 24 h: it
reduced apoptosis and necrosis of proximal renal tubular cells[138].
Thus, patients
at risk of CI-AKI undergoing cardiovascular procedures, using either the
iso-osmolar iodixanol or the low-osmolar iohexol have been treated either with
prednisone + hydration or hydration alone. Oral prednisone 1 mg/kg was
administered 12 hours before, at 6 am on the same day, and 24 hours following
the procedure. Serum creatinine was tested immediately before and again 24-48
hours after the procedure; neutrophil gelatinase-associated lipocalin (NGAL),
kidney injury molecule-1 (KIM-1), protein and albumin were assayed in spot
urine before and 6 hours after the procedure. In the absence of AKI, NGAL and
KIM-1 tended to rise after the procedure, but to a lesser degree in the
patients treated with prednisone (delta NGAL: hydration = +128%, prednisone =
+46%; p = 0.26; delta KIM-1: hydration = +99%, prednisone = +11%; p
= 0.02)[137]. These findings suggest that tubular damage was
attenuated in the steroid-treated patients.
Protective
effects of trimetazidin
Trimetazidine is a drug used in clinical practice for treating angina
pectoris, sold under the brand name Vastarel. It is a cytoprotective
anti-ischemic agent that increases cell tolerance to ischaemia by maintaining
cellular homeostasis[139]. Experimental studies demonstrated that
trimetazidine prevents the deleterious effects of ischaemia-reperfusion at the
mitochondrial levels in a dose-dependent manner. This protective effect appears
to be the key factor through which this drug exerts its cytoprotective activity[140].
It has been demonstrated that trimetazidine exerts also a potent antioxidant
activity on various tissue preparations, protecting the epithelium from the
deleterious effect of oxygen radicals[141].
Onbasili et
al[142] studied the efficacy of trimetazidine in the prevention
of CI-AKI in 82 patients with high SCr undergoing coronary
angiography/angioplasty. The drug was given orally, 20 mg thrice daily, for 72
hours starting 48 hours before the procedure; all patients were given i.v.
isotonic saline (1 mL/kg). CI-AKI developed in only one of 40 patients who were
given trimetazidine (2.5%) and in seven of 42 controls (17%).
More recently
Rahman et al[143] have conducted a prospective randomized,
controlled trial to evaluate the efficacy of trimetazidine in the prevention of
CI-AKI in 400 patients with raised SCr undergoing coronary angiography: 200
patients were treated with Trimetazidine plus normal saline and 200 patients
(control) were given only normal saline. It was found that the incidence of
CI-AKI was significantly (p<0.05) reduced by trimetazidine administration
with saline in comparison with saline alone: 4% vs 14%.
Trimetazidine
inhibits the excessive release of oxygen-free radicals, increases glucose
metabolism, limits intracellular acidosis, protects ATP stores, reduces
membrane lipid peroxidation and inhibits neutrophil infiltration after
ischaemia-reperfusion[142].
The
effectiveness of trimetazidin for the prevention of CI-AKI has been
histopathologically demonstrated in rats[144]. The histopathological
shape of kidney tissues were similar in rats treated with IRCA plus
trimetazidin and in rats not treated with IRCA.
Measures
to decrease the outer renal medullary hypoxia
The osmotic diuresis induced by IRCA causes an increased delivery of
tubular fluid to the thick ascending limb of Henles loops, thereby increasing
the local active sodium reabsorption and consequently O2 demand,
thereby aggravating outer renal medullary hypoxia (Figure 1). Thus, it has been
thought that furosemide, by decreasing sodium reabsorption in this tubular
segment[145,146], would reduce medullary O2 consumption
and decrease renal medullary hypoxia. Unfortunately, several studies have
demonstrated no protection against CI-AKI when utilizing furosemide or even
deleterious effects[147-149], mainly related to the salt depletion
caused by diuretics. To overcome the problem of hypovolemia caused by the diuretic,
a perfect combination of hydration plus furosemide has been suggested, by
delivering i.v. fluid in an amount exactly matched to the volume of urine
produced by the patient under the effect of furosemide[150,151].
This procedure is accomplished by a special device, called RenalGuard, that
would guide the physician in achieving high urine output while simultaneously
balancing urine output and venous fluid infusion to prevent hypovolemia[99].
Measures
to prevent IRCA nephrotoxicity by antioxidants
Since ROS have been proven to play an important role in the renal
damage caused by IRCA, it has been thought that antioxidants would prevent
CI-AKI[105].
The mostly
widely used antioxidant is N-acetylcysteine that may act either as a
free-radical scavenger or as a reactive sulfhydryl compound as well as a factor
able to increase the vasodilating effect of NO[152]. Despite
controversial results reported in the literature[105], it has been
suggested to use N-acetylcysteine in high-risk patients either with an oral
dose of 600 mg twice daily the day before and the day of procedure[20]
or, in patients unable to take the drug orally, with an IV dose of 150 mg/kg
over half an hour before the procedure or 50 mg/kg administered over 4 hours[153].
Conflicting
results have been obtained with the use of the antioxidant ascorbic acid at a
dosage of 3 g orally 2 hours before the procedure and 2 g during the night and
in the morning after the procedure[154-158].
The oral
administration of either 350 mg/day of -tocopherol or 300 mg/day of -tocopherol
(5 days prior to the coronary procedure and continued for a further 2 days
post-procedure) in combination with 0.9% saline has been demonstrated to be
effective in protecting against CI-AKI in patients with chronic kidney disease
undergoing coronary procedures with low-osmolar iopromide[159,160].
Mesna
(mercapto-ethane-sulfonate Na) is an agent with antioxidant properties that has
been shown to reduce free radicals and restore reduced glutathione levels after
ischemic renal failure[161]. The i.v. administration of 1,600 mg
Mesna versus placebo, together with i.v. hydration with 0.9% saline, resulted
in the occurrence of CI-AKI in 7 patients in the placebo group and none in the
Mesna group[162].
Nebivolol, a third-generation 1-adrenergic
receptor antagonist, seems to have a protective effect on the kidney against
CI-AKI through its antioxidant and NO-mediated vasodilating action[163].
At a dosage of 5 mg/day for one week or 5 mg every 24 hours for 4 days it
decreased the incidence of CI-AKI in patients with renal dysfunction undergoing
coronary angiography[105,164,165].
Recent studies
have shown a beneficial effect of statins to prevent CI-AKI in patients
undergoing percutaneous coronary intervention[105,166,167]. When
patients undergoing percutaneous coronary intervention have been given
pre-treatment with atorvastatin, 80 mg 12 hours before intervention with
another 40 mg pre-procedure, followed by long-term treatment of 40 mg/day,
CI-AKI was prevented[168].
Reversal
of IRCA toxicity on human renal proximal tubular cells by white grape
juice extract
In vivo studies using rats fed with grape seed proanthocyanidin extract[169]
have been found to be protective against renal tissue damage due to IRCA. Since
grape juice is a rich source of antioxidants and has been shown to increase
serum antioxidant capacity in adults[170] and since it has also been
demonstrated that Concord grape juice may activate Akt/PKB kinase by increasing
its phosphorylation at Ser 473[171], it seemed feasible that grape
juice may afford protection against the toxic effects of IRCA. Recent work from
our laboratory investigated the action of a white grape juice extract (WGJe) on
culture human renal proximal tubule cells (HK-2) treated with the high-osmolar
IRCA sodium diatrizoate, to evaluate any changes in the signaling pathways in
these cells[172]. WGJe caused an increase in phosphorylation of the
prosurvival kinases Akt and ERK1/2 in HK-2 cells. Treatment of HK-2 cells with
75 mg Iodine/ml sodium diatrizoate for 2.5 h and then further incubation (for
27.5 h) after removal of the IRCA caused a drastic decrease in cell viability.
However, pre-treatment with WGJe, prior to incubation with diatrizoate,
dramatically improved cell viability. Analysis of key signalling molecules by
Western blotting showed that diatrizoate caused a drastic decrease in
phosphorylation of Akt (at Ser473), FoxO1 (at Thr24) and FoxO3a (at Thr32)
during the initial 2.5 h incubation period, and WGJe pre-treatment caused a
reversal of these effects. Further analysis by Western blotting of samples from
HK-2 cells cultured for longer periods of time (for up to 27.5h after an
initial 2.5h exposure to diatrizoate with or without WGJe pre-treatment) showed
that WGJe pre-treatment caused a negative effect on phosphorylation of p38,
NF-kB (at Ser276) and ERK1/2 whilst having a positive effect on the
phosphorylation of Akt, FoxO1/FoxO3a and maintained levels of Pim-1 kinase[172].
Acknowledgements
Dr. Ashour Michael is currently recipient of a Research Check from
Magna Graecia University of Catanzaro, Italy. Authors contributions: M.A.
and A.M. wrote most of the paper; T.F. wrote the abstract, took the decisions
about tables/figure to insert, wrote the papers part related to the prevention
and performed the literature search.
CONFLICT OF INTERESTS
The Authors have no conflicts of interest to declare.
REFERENCES
1 Katzberg
RW. Contrast medium-induced nephrotoxicity: which pathway? Radiology 2005; 235:
752-5
2 Persson
PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy.
Kidney international 2005; 68: 14-22
3 Solomon
R. The role of osmolality in the incidence of contrast-induced nephropathy: a
systematic review of angiographic contrast media in high risk patients. Kidney
international 2005; 68: 2256-63
4 Deray
G, Martinez F, Cacoub P, Baumelou B, Baumelou A, Jacobs C. A
role for adenosine calcium and ischemia in radiocontrast-induced intrarenal
vasoconstriction. American journal of nephrology 1990;
10: 316-22.
5. Solomon
R. Contrast-induced acute kidney injury: is there a risk after intravenous
contrast? Clin J Am Soc Nephrol 2008;3:1242-3.
6. Andreucci
M, Faga T, Pisani A, Sabbatini M, Michael A. Acute Kidney Injury by Radiographic
Contrast Media: Pathogenesis and Prevention. BioMed Research Int 2014, 2014,
Article ID 362725, 21 pages http://dx.doi.org/10.1155/2014/362725.
7. Fuiano
G, Mancuso D, Indolfi C, Mongiardo A, Sabbatini M, Conte G, De Nicola L,
Minutolo R, Mazza G, Cianfrone P, Andreucci M. Early
detection of progressive renal dysfunction in patients with coronary artery
disease. Kidney international 2005; 68: 2773-80.
8. Katzberg
RW. Urography into the 21st century: new contrast media, renal handling,
imaging characteristics, and nephrotoxicity. Radiology 1997;
204: 297-312.
9. Michael
A, Faga T, Pisani A, Riccio E, Bramanti P, Sabbatini M, Navarra M, Andreucci M.
Molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast
media. BioMed research international 2014; 2014: 249810.
10. Morcos
SK. Contrast-induced nephropathy: are there differences between low osmolar and
iso-osmolar iodinated contrast media? Clinical radiology
2009; 64: 468-72.
11. Andreucci
M. Side effects of radiographic contrast media. BioMed research international
2014; 2014: 872574.
12. Andreucci
M, Solomon R, Tasanarong A. Side Effects of Radiographic Contrast Media:
Pathogenesis, Risk Factors, and Prevention. BioMed research international 2014;
2014: 741018.
13. Andreucci
M. [Radiographic contrast nephropathy]. G Ital Nefrol 2014,
31(5).
14. Andreucci
M, Faga T, De Sarro GB, Michael A. The toxicity of
Radiographic Contrast Agents in the Clinical Practice. J Nephrol Advances 2015; in press.
15. Andreucci
M. [Contrast media and nephrotoxicity: a molecular conundrum]. G Ital Nefrol
2011, 28(4): 355.
16. Group
KDIGOKAKIW. KDIGO Clinical Practice Guideline for Acute
Kidney Injury. Kidney international 2012; 2: 1-138.
17. Taliercio
CP, Vlietstra RE, Fisher LD, Burnett JC. Risks for renal
dysfunction with cardiac angiography. Annals of
internal medicine 1986; 104: 501-4.
18. McCullough
P. Outcomes of contrast-induced nephropathy: experience in patients undergoing
cardiovascular intervention. Catheter Cardiovasc Interv 2006; 67: 335-43.
19. Cochran ST, Wong WS, Roe DJ. Predicting angiography-induced acute renal function impairment:
clinical risk model. AJR American journal of
roentgenology 1983; 141: 1027-33.
20. Gleeson
TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR
American journal of roentgenology 2004; 183: 1673-89.
21. Delanaye
P, Cavalier E, Cristol JP, Delanghe JR. Calibration and precision of serum
creatinine and plasma cystatin C measurement: impact on the estimation of
glomerular filtration rate. Journal of nephrology 2014.
22. Seronie-Vivien
S, Delanaye P, Pieroni L, Mariat C, Froissart M, Cristol JP, Sfbc Biology of
renal function renal failure working group. Cystatin C: current position and
future prospects. Clinical chemistry and laboratory medicine: CCLM / FESCC
2008; 46: 1664-86.
23. Inker
LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi
J, Van Lente F, Zhang YL, Coresh J, Levey, AS, Ckd-Epi Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin
C. The New England journal of medicine 2012; 367:
20-9.
24. Masson
I, Maillard N, Tack I, Thibaudin L, Dubourg L, Delanaye P, Cavalier E, Bonneau
C, Kamar N, Morelon E, Moranne O, Alamartine E, Mariat C. GFR estimation using
standardized cystatin C in kidney transplant recipients. American
journal of kidney diseases 2013; 61: 279-84.
25. Mindikoglu
AL, Dowling TC, Weir MR, Seliger SL, Christenson RH, Magder LS. Performance of chronic kidney disease epidemiology collaboration
creatinine-cystatin C equation for estimating kidney function in cirrhosis.
Hepatology 2014; 59: 1532-42.
26. Obiols
J, Bargnoux AS, Kuster N, Fesler P, Pieroni L, Badiou S, Dupuy
AM, Ribstein J, Cristol JP. Validation of a new standardized cystatin C
turbidimetric assay: evaluation of the three novel CKD-EPI equations in
hypertensive patients. Clinical biochemistry 2013; 46:
1542-7.
27. Fan
L, Inker LA, Rossert J, Froissart M, Rossing P, Mauer M, Levey AS. Glomerular filtration rate estimation using cystatin C alone or
combined with creatinine as a confirmatory test. Nephrology,
dialysis, transplantation 2014; 29: 1195-203.
28. KDIGO
2012 Clinical Practice Guideline for the Evaluation and Management of Chronic
Kidney Disease. Kidney Int volume 3 Supplement issue 1, January 2013
29. Eriksen
BO, Mathisen UD, Melsom T, Ingebretsen OC, Jenssen TG, Njolstad I, Solbu MD,
Toft I. Cystatin C is not a better estimator of GFR than plasma creatinine in
the general population. Kidney international 2010; 78: 1305-11.
30. Ribichini
F, Gambaro G, Graziani MS, Pighi M, Pesarini G, Pasoli P, Anselmi M, Ferrero V,
Yabarek T, Sorio A, Rizzotti P, Lupo A, Vassanelli C. Comparison of serum
creatinine and cystatin C for early diagnosis of contrast-induced nephropathy
after coronary angiography and interventions. Clinical
chemistry 2012; 58: 458-64.
31. Kuhn
MJ, Chen N, Sahani DV, Reimer D, van Beek EJ, Heiken JP, So GJ. The PREDICT
study: a randomized double-blind comparison of contrast-induced nephropathy
after low- or isoosmolar contrast agent exposure. AJR
American journal of roentgenology 2008; 191: 151-7.
32. Byrd
L, Sherman RL. Radiocontrast-induced acute renal failure: a clinical and
pathophysiologic review. Medicine (Baltimore) 1979; 58:
270-9.
33. Harkonen
S, Kjellstrand C. Contrast nephropathy. American journal of
nephrology 1981; 1: 69-77.
34. Andreucci
VE, Fuiano G, Russo D, Andreucci M. Vasomotor nephropathy in the elderly. Nephrology, dialysis, transplantation 1998; 13 Suppl 7: 17-24.
35. Andreucci
VE, Fuiano G, Stanziale P, Andreucci M. Role of renal biopsy in the diagnosis
and prognosis of acute renal failure. Kidney international Supplement 1998; 66:
S91-5.
36. Andreucci
VE, Russo D, Cianciaruso B, Andreucci M. Some sodium,
potassium and water changes in the elderly and their treatment. Nephrology, dialysis, transplantation 1996; 11 Suppl 9: 9-17.
37. Andreucci
M, Federico S, Andreucci VE. Edema and acute renal failure.
Seminars in nephrology 2001; 21: 251-6.
38. Katzberg
RW, Barrett BJ. Risk of iodinated contrast material--induced
nephropathy with intravenous administration. Radiology 2007; 243: 622-8.
39. Andreucci
M, Faga T, Pisani A, Sabbatini M, Michael A. Pathogenesis of Acute Renal
Failure induced by iodinated radiographic contrast media. Austin J Nephrol
Hypertens 2014; 1(1): 1005.
40. Andreucci
M, Faga T, Pisani A, Sabbatini M, Russo D, Michael A. Prevention of
Contrast-Induced Nephropathy through a knowledge of its pathogenesis and risk
factors. Scientific World Journal 2014; 823169, 16 pages,
http://dx.doi.org/10.1155/2014/823169
41. Sabbatini
M, Uccello F, Serio V, Troncone G, Varone V, Andreucci M, Faga T, Pisani A.
Effects of mycophenolate mofetil on acute ischaemia-reperfusion injury in rats
and its consequences in the long term. Nephrol Dial
Transplant. 2010 May; 25(5): 1443-50
42. Giaccia
AJ, Simon MC, Johnson R. The biology of hypoxia: the role of oxygen sensing in
development, normal function, and disease. Genes Dev 2004; 18: 2183-94.
43. Sabbatini
M, Santillo M, Pisani A, Paterno R, Uccello F, Seru R, Matrone G, Spagnuolo G,
Andreucci M, Serio V, Esposito P, Cianciaruso B, Fuiano G, Avvedimento EV.
Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury.
American journal of physiology Renal physiology 2006;
290(6): F1408-15.
44. Pisani
A, Sabbatini M, Riccio E, Rossano R, Andreucci M, Capasso C, De Luca V,
Carginale V, Bizzarri M, Borrelli A, Schiattarella A, Santangelo M, Mancini A.
Effect of a recombinant manganese superoxide dismutase on prevention of
contrast-induced acute kidney injury. Clinical and experimental nephrology 2014;18:424-31.
45. Heyman
SN, Rosen S, Khamaisi M, Idee JM, Rosenberger C. Reactive oxygen species and
the pathogenesis of radiocontrast-induced nephropathy. Investigative
radiology 2010; 45: 188-95.
46. Dawson
P, Becker A, Holton JM. The effect of contrast media on the
growth of bacteria. The British journal of radiology
1983; 56: 809-15.
47. Sendeski MM. Pathophysiology of renal
tissue damage by iodinated contrast media. Clinical and experimental pharmacology & physiology 2011; 38:
292-9.
48. Pisani
A, Riccio E, Andreucci M, Faga T, Ashour M, Di Nuzzi A, Mancini A, Sabbatini M.
Role of reactive oxygen species in pathogenesis of radiocontrast-induced
nephropathy. BioMed research international 2013; 2013: 868321.
49. Pacher
P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease.
Physiological reviews 2007; 87: 315-424.
50. Franke
RP, Fuhrmann R, Hiebl B, Jung F. Influence of radiographic contrast media
(iodixanol und iomeprol) on the morphology of human arterial and venous
endothelial cells on extracellular matrix in vitro. Clinical
hemorheology and microcirculation 2011; 48: 41-56.
51. Franke
RP, Fuhrmann R, Park JW, Rickert D, Hiebl B, Jung F. The
effect of radiographic contrast media on the morphology of human venous
endothelial cells. Clinical hemorheology and
microcirculation 2007; 37: 329-38.
52. Ramponi
S, Grotti A, Morisetti A, Vultaggio S, Lorusso V. Effects of iodinated contrast
media on endothelium: An in vitro study. Toxicology in vitro: an
international journal published in association with BIBRA 2007; 21: 191-6.
53. Sumimura
T, Sendo T, Itoh Y, Oka M, Oike M, Ito Y, Oishi R. Calcium-dependent injury of
human microvascular endothelial cells induced by a variety of iodinated
radiographic contrast media. Investigative radiology 2003;
38: 366-74.
54. Gospos
C, Freudenberg N, Staubesand J, Mathias K, Papacharlampos X. The
effect of contrast media on the aortic endothelium of rats. Radiology 1983; 147: 685-8.
55. Heyman
SN, Clark BA, Kaiser N, Spokes K, Rosen S, Brezis M, Epstein FH. Radiocontrast
agents induce endothelin release in vivo and in vitro. Journal of the American
Society of Nephrology: JASN 1992; 3: 58-65.
56. Reinhart
WH, Pleisch B, Harris LG, Lutolf M. Influence of contrast media (iopromide,
ioxaglate, gadolinium-DOTA) on blood viscosity,
erythrocyte morphology and platelet function. Clinical
hemorheology and microcirculation 2005; 32: 227-39.
57. Aspelin
P. Effect of ionic and non-ionic contrast media on red cell deformability in
vitro. Acta radiologica: diagnosis 1979;20:1-12.
58. Aspelin
P, Nilsson PE, Schmid-Schonbein H, Schroder S, Simon R. Effect of four
non-ionic contrast media on red blood cells in vitro. III. Deformability. Acta radiologica Supplementum 1987; 370: 89-91.
59. Hardeman
MR, Goedhart P, Koen IY. The effect of low-osmolar ionic and
nonionic contrast media on human blood viscosity, erythrocyte morphology, and
aggregation behavior. Investigative radiology 1991;
26: 810-9.
60. Jung
F, Mrowietz C, Rickert D, Hiebl B, Park JW, Franke RP. The
effect of radiographic contrast media on the morphology of human erythrocytes.
Clinical hemorheology and microcirculation 2008; 38: 1-11.
61. Kerl
JM, Nguyen SA, Lazarchick J, Powell JW, Oswald MW, Alvi F, Costello P, Vogl TJ,
Schoepf UJ. Iodinated contrast media: effect of osmolarity and injection
temperature on erythrocyte morphology in vitro. Acta
radiologica 2008; 49: 337-43.
62. Losco
P, Nash G, Stone P, Ventre J. Comparison of the effects of radiographic
contrast media on dehydration and filterability of red blood cells from donors
homozygous for hemoglobin A or hemoglobin S. American journal of hematology
2001; 68: 149-58.
63. Strickland
NH, Rampling MW, Dawson P, Martin G. Contrast media-induced effects on blood
rheology and their importance in angiography. Clinical
radiology 1992; 45: 240-2.
64. Franke
RP, Scharnweber T, Fuhrmann R, Mrowietz C, Jung F. Effect of radiographic
contrast media (Iodixanol, Iopromide) on the spectrin/actin-network of the
membranous cytoskeleton of erythrocytes. Clinical
hemorheology and microcirculation 2013; 54: 273-85.
65. Bennett
V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for
integrating cells into tissues. Physiological reviews 2001;
81: 1353-92.
66. Jiang
J, Magilnick N, Tsirulnikov K, Abuladze N, Atanasov I, Ge P, Narla M, Pushkin
A, Zhou ZH, Kurtz I. Single particle electron microscopy analysis of the bovine
anion exchanger 1 reveals a flexible linker connecting the cytoplasmic and
membrane domains. PloS one 2013;8:e55408.
67. Anong
WA, Franco T, Chu H, Weis TL, Devlin EE, Bodine DM, An X, Mohandas N, Low PS.
Adducin forms a bridge between the erythrocyte membrane and its cytoskeleton
and regulates membrane cohesion. Blood 2009; 114: 1904-12.
68. Franke
RP, Scharnweber T, Fuhrmann R, Wenzel F, Kruger A, Mrowietz C, Jung F. Effect
of radiographic contrast media on the spectrin/band3-network of the membrane
skeleton of erythrocytes. PloS one 2014; 9: e89512.
69. Reinhart
WH. Peculiar red cell shapes: Fahraeus Lecture 2011. Clinical
hemorheology and microcirculation 2011; 49: 11-27.
70. Mrowietz
C, Franke RP, Jung F. Influence of different radiographic contrast media on the
echinocyte formation of human erythrocytes. Clinical
hemorheology and microcirculation 2012; 50: 35-47.
71. Heyman
SN, Brezis M, Epstein FH, Spokes K, Silva P, Rosen S. Early
renal medullary hypoxic injury from radiocontrast and indomethacin.
Kidney international 1991; 40: 632-42.
72. Tervahartiala
P, Kivisaari L, Kivisaari R, Vehmas T, Virtanen I. Structural changes in the
renal proximal tubular cells induced by iodinated contrast media. Nephron 1997; 76: 96-102.
73. Heinrich
MC, Kuhlmann MK, Grgic A, Heckmann M, Kramann B, Uder M. Cytotoxic effects of
ionic high-osmolar, nonionic monomeric, and nonionic iso-osmolar dimeric
iodinated contrast media on renal tubular cells in vitro. Radiology 2005; 235:
843-9.
74. Hardiek
K, Katholi RE, Ramkumar V, Deitrick C. Proximal tubule cell response to
radiographic contrast media. American journal of physiology Renal
physiology 2001; 280: F61-70.
75. Heyman
SN, Fuchs S, Jaffe R, Shina A, Ellezian L, Brezis M, Rosen S. Renal
microcirculation and tissue damage during acute ureteral obstruction in the
rat: effect of saline infusion, indomethacin and radiocontrast. Kidney international
1997; 51: 653-63.
76. Hizoh
I, Haller C. Radiocontrast-induced renal tubular cell apoptosis: hypertonic
versus oxidative stress. Investigative radiology 2002; 37:
428-34.
77. Yano
T, Itoh Y, Sendo T, Kubota T, Oishi R. Cyclic AMP reverses radiocontrast
media-induced apoptosis in LLC-PK1 cells by activating A kinase/PI3 kinase.
Kidney international 2003; 64: 2052-63.
78. Zhang
J, Duarte CG, Ellis S. Contrast medium- and mannitol-induced apoptosis in heart
and kidney of SHR rats. Toxicologic pathology 1999; 27:
427-35.
79. Andreucci
M, Faga T, Russo D, Bertucci B, Tamburrini O, Pisani A, Sabbatini M, Fuiano G,
Michael A. Differential activation of signaling pathways by low-osmolar and
iso-osmolar radiocontrast agents in human renal tubular cells. Journal of
Cellular Biochemistry 2014; 115(2): 281-9.
80. Cross
TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM. Serine/threonine protein kinases and apoptosis. Exp Cell Res
2000; 256: 34-41.
81. Datta
SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 13: 2905-27.
82. Kyriakis
JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction
pathways activated by stress and inflammation. Physiological
reviews 2001; 81: 807-69.
83. Woodgett
JE. Protein Kinase functions.: Oxford University
Press; 2000.
84. Andreucci
M, Michael A, Kramers C, Park KM, Chen A, Matthaeus T, Alessandrini A, Haq S,
Force T, Bonventre JV. Renal ischemia/reperfusion and ATP depletion/repletion
in LLC-PK(1) cells result in phosphorylation of FKHR
and FKHRL1. Kidney international 2003; 64: 1189-98.
85. Racusen
LC, Monteil C, Sgrignoli A, Lucskay M, Marouillat S, Rhim JG, Morin JP. Cell
lines with extended in vitro growth potential from human renal proximal tubule:
characterization, response to inducers, and comparison with established cell
lines. The Journal of laboratory and clinical medicine 1997;129:318-29.
86. Ryan
MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA, Torok-Storb B. HK-2: an
immortalized proximal tubule epithelial cell line from normal adult human
kidney. Kidney international 1994; 45: 48-57.
87. Andreucci
M, Fuiano G, Presta P, Lucisano G, Leone F, Fuiano L, Bisesti V, Esposito P,
Russo D, Memoli B, Faga T, Michael A. Downregulation of cell survival
signalling pathways and increased cell damage in hydrogen peroxide-treated
human renal proximal tubular cells by alpha-erythropoietin. Cell Prolif 2009;42:554-61.
88. Andreucci
M, Fuiano G, Presta P, Esposito P, Faga T, Bisesti V, Procino A, Altieri V,
Tozzo C, Memoli B, Michael A. Radiocontrast media cause dephosphorylation of
Akt and downstream signaling targets in human renal proximal tubular cells.
Biochem Pharmacol 2006; 72: 1334-42.
89. Mosmann
T. Rapid colorimetric assay for cellular growth and survival: application to
proliferation and cytotoxicity assays. J Immunol Methods
1983; 65: 55-63.
90. Yoon
S, Seger R. The extracellular signal-regulated kinase: multiple substrates
regulate diverse cellular functions. Growth Factors 2006; 24: 21-44.
91. Kyriakis
JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress
and inflammation: a 10-year update. Physiological reviews
2012; 92: 689-737.
92. Nowak
DE, Tian B, Jamaluddin M, Boldogh I, Vergara LA, Choudhary S, Brasier, AR. RelA
Ser276 phosphorylation is required for activation of a subset of
NF-kappaB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1
complexes. Mol Cell Biol 2008; 28: 3623-38.
93. Andreucci
M, Faga T, Lucisano G, Uccello F, Pisani A, Memoli B, Sabbatini M, Fuiano G,
Michael A. Mycophenolic acid inhibits the phosphorylation of NF-kappaB and JNKs
and causes a decrease in IL-8 release in H2O2-treated human renal proximal
tubular cells. Chem Biol Interact 2010; 185: 253-62.
94. Andreucci
M, Lucisano G, Faga T, Bertucci B, Tamburrini O, Pisani A, Sabbatini M, Salzano
S, Vitale M, Fuiano G. Michael A. Differential activation of signaling pathways
involved in cell death, survival and inflammation by radiocontrast media in
human renal proximal tubular cells. Toxicol Sci 2011; 119: 408-16.
95. Weston
CR, Davis RJ. The JNK signal transduction pathway.
Curr Opin Cell Biol 2007; 19: 142-9.
96. Zarubin
T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res
2005; 15: 11-8.
97. Gong
X, Celsi G, Carlsson K, Norgren S, Chen M. N-acetylcysteine amide protects
renal proximal tubular epithelial cells against iohexol-induced apoptosis by
blocking p38 MAPK and iNOS signaling. American journal of
nephrology 2010; 31: 178-88.
98. Lee
HC, Sheu SH, Yen HW, Lai WT, Chang JG. JNK/ATF2 pathway is involved in
iodinated contrast media-induced apoptosis. American journal
of nephrology 2010; 31: 125-33.
99. Andreucci
M, Faga T, Michael A. The Renal Problems in X-Ray Based Imaging Techniques
Using Iodinated Radiographic Contrast Agents. Open Access Journal of Science
and Technology 2015; in press.
100. Pflueger
A, Larson TS, Nath KA, King BF, Gross JM, Knox FG. Role of
adenosine in contrast media-induced acute renal failure in diabetes mellitus.
Mayo Clinic proceedings 2000; 75: 1275-83.
101. Khamaisi
M, Raz I, Shilo V, Shina A, Rosenberger C, Dahan R, Abassi Z, Meidan R, Lecht
S, Heyman SN. Diabetes and radiocontrast media increase endothelin converting
enzyme-1 in the kidney. Kidney international 2008; 74: 91-100.
102. Andreucci
M, Faga T, Pisani A, Sabbatini M, Michael A. The choice of
the iodinated radiographic contrast media to prevent Contrast-Induced
Nephropathy. Advances in Nephrology 2014; 691623, 11 pages,
http://dx.doi.org/10.1155/2014/691623
103. Martin-Mateo
MC, Sanchez-Portugal M, Iglesias S, de Paula A, Bustamante J. Oxidative stress
in chronic renal failure. Renal failure 1999; 21: 155-67.
104. Okamura
DM, Pennathur S, Pasichnyk K, Lopez-Guisa JM, Collins S, Febbraio M, Heinecke
J, Eddy AA. CD36 regulates oxidative stress and inflammation in
hypercholesterolemic CKD. Journal of the American Society of Nephrology
: JASN 2009; 20: 495-505.
105. Andreucci
M, Faga T, Sabbatini M, Pisani A, Russo D, Michael A. How to
prevent Contrast-Induced Nephropathy in clinical practice. J Clin
Nephrol Res 2014; 1(1): 1002.
106. Keaney
JJ, Hannon CM, Murray PT. Contrast-induced acute kidney injury: how much
contrast is safe? Nephrology, dialysis, transplantation 2013;
28: 1376-83.
107. Yang
D, Yang D, Jia R, Tan J. Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates
contrast-induced acute kidney injury. Journal of nephrology
2013; 26: 877-85.
108. Duan
SB, Liu FY, Luo JA, Wu HW, Liu RH, Peng YM, Yang XL. Nephrotoxicity
of high- and low-osmolar contrast media. The
protective role of amlodipine in a rat model. Acta
radiologica 2000; 41: 503-7.
109. Yokomaku
Y, Sugimoto T, Kume S, Araki S, Isshiki K, Chin-Kanasaki M, Sakaguchi M, Nitta
N, Haneda M, Koya D, Uzu T, Kashiwagi A. Asialoerythropoietin prevents
contrast-induced nephropathy. Journal of the American Society of Nephrology : JASN 2008; 19: 321-8.
110. Sharples
EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D,
Harwood S, Raftery M, Thiemermann C, Yaqoob MM. Erythropoietin protects the
kidney against the injury and dysfunction caused by ischemia-reperfusion.
Journal of the American Society of Nephrology : JASN
2004; 15: 2115-24.
111. Yang
CW, Li C, Jung JY, Shin SJ, Choi BS, Lim SW, Sun BK, Kim YS, Kim J, Chang YS,
Bang BK. Preconditioning with erythropoietin protects against subsequent
ischemia-reperfusion injury in rat kidney. FASEB journal :
official publication of the Federation of American Societies for Experimental
Biology 2003; 17: 1754-5.
112. Bagnis
C, Beaufils H, Jacquiaud C, Adabra Y, Jouanneau C, Le Nahour G, Jaudon MC,
Bourbouze R, Jacobs C, Deray G. Erythropoietin enhances recovery after
cisplatin-induced acute renal failure in the rat. Nephrology,
dialysis, transplantation 2001; 16: 932-8.
113. Goldfarb
M, Rosenberger C, Ahuva S, Rosen S, Heyman SN. A role for
erythropoietin in the attenuation of radiocontrast-induced acute renal failure
in rats. Renal failure 2006; 28: 345-50.
114. Kodama
A, Watanabe H, Tanaka R, Tanaka H, Chuang VT, Miyamoto Y, Wu Q, Endo M,
Hamasaki K, Ishima Y, Fukagawa M, Otagiri, M, Maruyama T. A human serum
albumin-thioredoxin fusion protein prevents experimental contrast-induced
nephropathy. Kidney international 2013; 83: 446-54.
115. Ellis
JH, Cohan RH. Prevention of contrast-induced nephropathy: an overview. Radiol
Clin North Am 2009; 47: 801-11, v.
116. Solomon
R, Dauerman HL. Contrast-induced acute kidney injury.
Circulation 2010; 122: 2451-5.
117. Mueller
C. Prevention of contrast-induced nephropathy with volume supplementation.
Kidney international Supplement 2006: S16-9.
118. Merten
GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Van
Moore A, Simonton CA 3rd, Rittase RA, Norton HJ, Kennedy TP. Prevention of
contrast-induced nephropathy with sodium bicarbonate: a randomized controlled
trial. JAMA 2004; 291: 2328-34.
119. Masuda
M, Yamada T, Mine T, Morita T, Tamaki S, Tsukamoto Y, Okuda K, Iwasaki Y, Hori
M, Fukunami M. Comparison of usefulness of sodium bicarbonate versus sodium
chloride to prevent contrast-induced nephropathy in patients undergoing an emergent
coronary procedure. The American journal of cardiology 2007;
100: 781-6.
120. Ozcan
EE, Guneri S, Akdeniz B, Akyildiz IZ, Senaslan O, Baris N, Aslan O, Badak O.
Sodium bicarbonate, N-acetylcysteine, and saline for prevention of
radiocontrast-induced nephropathy. A comparison of 3 regimens
for protecting contrast-induced nephropathy in patients undergoing coronary
procedures. A single-center prospective controlled trial. Am Heart J 2007; 154: 539-44.
121. Tamura
A, Goto Y, Miyamoto K, Naono S, Kawano Y, Kotoku M, Watanabe T, Kadota J.
Efficacy of single-bolus administration of sodium bicarbonate to prevent
contrast-induced nephropathy in patients with mild renal insufficiency
undergoing an elective coronary procedure. The American
journal of cardiology 2009; 104: 921-5.
122. Navaneethan
SD, Singh S, Appasamy S, Wing RE, Sehgal AR. Sodium bicarbonate therapy for
prevention of contrast-induced nephropathy: a systematic review and
meta-analysis. American journal of kidney diseases 2009; 53:
617-27.
123. Hoste
EA, De Waele JJ, Gevaert SA, Uchino S, Kellum JA. Sodium bicarbonate for
prevention of contrast-induced acute kidney injury: a systematic review and
meta-analysis. Nephrology, dialysis, transplantation 2010;
25: 747-58.
124. Joannidis
M, Schmid M, Wiedermann CJ. Prevention of contrast media-induced nephropathy by
isotonic sodium bicarbonate: a meta-analysis. Wien Klin Wochenschr 2008; 120:
742-8.
125. Assadi
F. Acetazolamide for prevention of contrast-induced nephropathy: a new use for
an old drug. Pediatr Cardiol 2006; 27: 238-42.
126. Pakfetrat
M, Nikoo MH, Malekmakan L, Tabandeh M, Roozbeh J, Nasab MH, Ostovan MA, Salari
S, Kafi M, Vaziri NM, Adl F, Hosseini M, Khajehdehi P. A comparison of sodium
bicarbonate infusion versus normal saline infusion and its combination with
oral acetazolamide for prevention of contrast-induced nephropathy: a
randomized, double-blind trial. Int Urol Nephrol 2009; 41: 629-34.
127. Jang
JS, Jin HY, Seo JS, Yang TH, Kim DK, Kim TH, Urm SH, Kim DS, Kim DK, Seol SH,
Kim DI, Cho KI, Kim BH, Park YH, Je HG, Ahn JM, Kim WJ, Lee JY, Lee SW. Sodium
bicarbonate therapy for the prevention of contrast-induced acute kidney injury
- a systematic review and meta-analysis. Circ J 2012; 76: 2255-65.
128. Briguori
C, Airoldi F, D'Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I,
Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A. Renal
Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a
randomized comparison of 3 preventive strategies. Circulation 2007; 115:
1211-7.
129. Reddan
D, Laville M, Garovic VD. Contrast-induced nephropathy and its prevention: What
do we really know from evidence-based findings? Journal of
nephrology 2009; 22: 333-51.
130. Zoungas
S, Ninomiya T, Huxley R, Cass A, Jardine M, Gallagher M, Patel A,
Vasheghani-Farahani A, Sadigh G, Perkovic V. Systematic review: sodium
bicarbonate treatment regimens for the prevention of contrast-induced
nephropathy. Annals of internal medicine 2009; 151: 631-8.
131. Brar
SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N, Ree M, Shah AI,
Burchette RJ. Sodium bicarbonate vs sodium chloride for the prevention of
contrast medium-induced nephropathy in patients undergoing coronary angiography:
a randomized trial. JAMA 2008; 300: 1038-46.
132. Brar
SS, Hiremath S, Dangas G, Mehran R, Brar SK, Leon MB. Sodium bicarbonate for
the prevention of contrast induced-acute kidney injury: a systematic review and
meta-analysis. Clin J Am Soc Nephrol 2009; 4: 1584-92.
133. Shavit
L, Korenfeld R, Lifschitz M, Butnaru A, Slotki I. Sodium bicarbonate versus
sodium chloride and oral N-acetylcysteine for the prevention of
contrast-induced nephropathy in advanced chronic kidney disease. J Interv
Cardiol 2009; 22: 556-63.
134. Vasheghani-Farahani
A, Sadigh G, Kassaian SE, Khatami SM, Fotouhi A, Razavi SA, Mansournia MA,
Yamini-Sharif A, Amirzadegan A, Salarifar M, Sadeghian S, Davoodi G, Borumand
MA, Esfehani FA, Darabian S. Sodium bicarbonate plus isotonic saline versus
saline for prevention of contrast-induced nephropathy in patients undergoing
coronary angiography: a randomized controlled trial. American
journal of kidney diseases 2009; 54: 610-8.
135. From
AM, Bartholmai BJ, Williams AW, Cha SS, Pflueger A, McDonald FS. Sodium
bicarbonate is associated with an increased incidence of contrast nephropathy:
a retrospective cohort study of 7977 patients at mayo clinic. Clin J Am Soc
Nephrol 2008; 3: 10-8.
136. Briguori
C, Quintavalle C, Donnarumma E, Condorelli G. Novel Biomarkers for
Contrast-Induced Acute Kidney Injury. BioMed research international 2014; 2014:
568738.
137. Ribichini
F, Gambaro A, Pighi M, Pesarini G, Ferraro PM, Zuppi C, Baroni S, Penitente R,
Ferrero V, Vassanelli C. Effects of prednisone on biomarkers of tubular damage
induced by radiocontrast in interventional cardiology. Journal
of nephrology 2013; 26: 586-93.
138. Kumar
S, Allen DA, Kieswich JE, Patel NS, Harwood S, Mazzon E, Cuzzocrea S, Raftery
MJ, Thiemermann C, Yaqoob MM. Dexamethasone ameliorates renal
ischemia-reperfusion injury. Journal of the American Society of Nephrology : JASN 2009; 20: 2412-25.
139. Clauser
P, Harpey C. Antioxidant properties of an antiischaemic agent: trimetazidine.
Advances in experimental medicine and biology 1990; 264: 247-50.
140. Elimadi
A, Settaf A, Morin D, Sapena R, Lamchouri F, Cherrah Y, Tillement JP.
Trimetazidine counteracts the hepatic injury associated with
ischemia-reperfusion by preserving mitochondrial function. The
Journal of pharmacology and experimental therapeutics 1998; 286: 23-8.
141. Aubert
A, Bernard C, Clauser P, Harpey C, Vaudry H. Effect of phenazine methosulfate
on electrophysiological activity of the semicircular canal: antioxidant
properties of trimetazidine. European journal of pharmacology
1989; 174: 215-25.
142. Onbasili
AO, Yeniceriglu Y, Agaoglu P, Karul A, Tekten T, Akar H, Discigil G.
Trimetazidine in the prevention of contrast-induced nephropathy after coronary
procedures. Heart 2007; 93: 698-702.
143. Rahman
MM, Haque SS, Rokeya B, Siddique MA, Banerjee SK, Ahsan SA, Rahman F, Mahmood
M, Ahmed K, Bhuiyan MM, Joarder AI, Debnath RC. Trimetazidine in the prevention
of contrast induced nephropathy after coronary angiogram. Mymensingh medical journal : MMJ 2012; 21: 292-9.
144. Akgullu
C, Saruhan T, Eryilmaz U, Boyacioglu M, Onbasili OA, Meteoglu I, Kum C. The first histopathological evidence of trimetazidine for the
prevention of contrast-induced nephropathy. Renal
failure 2014; 36: 575-80.
145. Andreucci
M, Russo D, Fuiano G, Minutolo R, Andreucci VE. Diuretics in
renal failure. Mineral and electrolyte metabolism
1999; 25: 32-8.
146. Andreucci
M, Faga T, Perticone F, Michael A. Radiographic contrast agents, drugs useful
for diagnostics, but with contrast-induced nephropathy as side effect. J Nephro
Urol 2014, 1(2): 11.
147. Solomon
R, Werner C, Mann D, D'Elia J, Silva P. Effects of saline, mannitol, and
furosemide to prevent acute decreases in renal function induced by
radiocontrast agents. The New England journal of medicine
1994; 331: 1416-20.
148. Weinstein
JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in
radiocontrast nephropathy. Nephron 1992;62:413-5.
149. Weisberg
LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with
and without diabetes mellitus. Kidney international 1994; 45: 259-65.
150. Briguori
C, Visconti G, Focaccio A, Airoldi F, Valgimigli M, Sangiorgi GM, Golia B,
Ricciardelli B, Condorelli G, Remedial Ii Investigators. Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II):
RenalGuard System in high-risk patients for contrast-induced acute kidney
injury. Circulation 2011; 124: 1260-9.
151. Marenzi
G, Ferrari C, Marana I, Assanelli E, De Metrio M, Teruzzi G, Veglia F,
Fabbiocchi F, Montorsi P, Bartorelli AL. Prevention of contrast nephropathy by
furosemide with matched hydration: the MYTHOS (Induced Diuresis With Matched
Hydration Compared to Standard Hydration for Contrast Induced Nephropathy
Prevention) trial. JACC Cardiovascular interventions 2012; 5:
90-7.
152. Safirstein
R, Andrade L, Vieira JM. Acetylcysteine and nephrotoxic effects of radiographic
contrast agents--a new use for an old drug. The New England
journal of medicine 2000; 343: 210-2.
153. Baker
CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ. A rapid protocol for the
prevention of contrast-induced renal dysfunction: the RAPPID study. Journal of
the American College of Cardiology 2003; 41: 2114-8.
154. Spargias
K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Greenwood DC, Manginas A, Voudris
V, Pavlides G, Buller CE, Kremastinos D, Cokkinos DV. Ascorbic acid prevents
contrast-mediated nephropathy in patients with renal dysfunction undergoing
coronary angiography or intervention. Circulation 2004; 110: 2837-42.
155. Alexopoulos
E, Spargias K, Kyrzopoulos S, Manginas A, Pavlides G, Voudris V, Lerakis S,
McLean DS, Cokkinos DV. Contrast-induced acute kidney injury
in patients with renal dysfunction undergoing a coronary procedure and
receiving non-ionic low-osmolar versus iso-osmolar contrast media. Am J
Med Sci 2010; 339: 25-30.
156. Boscheri
A, Weinbrenner C, Botzek B, Reynen K, Kuhlisch E, Strasser RH. Failure of
ascorbic acid to prevent contrast-media induced nephropathy in patients with
renal dysfunction. Clin Nephrol 2007; 68: 279-86.
157. Jo
SH, Koo BK, Park JS, Kang HJ, Kim YJ, Kim HL, Chae IH, Choi DJ, Sohn DW, Oh BH,
Park YB, Choi YS, Kim HS. N-acetylcysteine versus AScorbic
acid for preventing contrast-Induced nephropathy in patients with renal
insufficiency undergoing coronary angiography NASPI study-a prospective
randomized controlled trial. Am Heart J 2009; 157:
576-83.
158. Sadat
U, Usman A, Gillard JH, Boyle JR. Does ascorbic acid protect against
contrast-induced acute kidney injury in patients undergoing coronary
angiography: a systematic review with meta-analysis of randomized, controlled
trials. Journal of the American College of Cardiology 2013; 62: 2167-75.
159. Tasanarong
A, Vohakiat A, Hutayanon P, Piyayotai D. New strategy of
alpha- and gamma-tocopherol to prevent contrast-induced acute kidney injury in
chronic kidney disease patients undergoing elective coronary procedures.
Nephrology, dialysis, transplantation 2013; 28: 337-44.
160. Kongkham
S, Sriwong S, Tasanarong A. Protective effect of alpha tocopherol on
contrast-induced nephropathy in rats. Nefrologia 2013; 33: 116-23.
161. Kabasakal
L, Sehirli AO, Cetinel S, Cikler E, Gedik N, Sener G. Mesna (2-mercaptoethane
sulfonate) prevents ischemia/reperfusion induced renal oxidative damage in
rats. Life Sci 2004; 75: 2329-40.
162. Ludwig
U, Riedel MK, Backes M, Imhof A, Muche R, Keller F. MESNA (sodium
2-mercaptoethanesulfonate) for prevention of contrast medium-induced
nephrotoxicity - controlled trial. Clin Nephrol 2011; 75: 302-8.
163. Toprak
O, Cirit M, Tanrisev M, Yazici C, Canoz O, Sipahioglu M, Uzum A, Ersoy R,
Sozmen EY. Preventive effect of nebivolol on contrast-induced
nephropathy in rats. Nephrology, dialysis,
transplantation 2008; 23: 853-9.
164. Avci
E, Yesil M, Bayata S, Postaci N, Arikan E, Cirit M. The role
of nebivolol in the prevention of contrast-induced nephropathy in patients with
renal dysfunction. Anadolu Kardiyol Derg 2011; 11: 613-7.
165. Gunebakmaz
O, Kaya MG, Koc F, Akpek M, Kasapkara A, Inanc MT, Yarlioglues M, Calapkorur B,
Karadag Z, Oguzhan A. Does nebivolol prevent contrast-induced nephropathy in
humans? Clin Cardiol 2012; 35: 250-4.
166. Andreucci
M. [Statins in CIN: a problem at least partly solved?]. G
Ital Nefrol 2013, 30(3).
167. Sabbatini
M, Pisani A, Uccello F, Serio V, Seru R, Paterno R, Cianciaruso B, Fuiano G,
Andreucci M. Atorvastatin improves the course of ischemic acute renal failure
in aging rats. Journal of the American Society of Nephrology: JASN 2004; 15:
901-9.
168. Patti G, Ricottini E, Nusca A, Colonna G, Pasceri
V, D'Ambrosio A, Montinaro A, Di Sciascio G. Short-term, high-dose Atorvastatin
pretreatment to prevent contrast-induced nephropathy in patients with acute
coronary syndromes undergoing percutaneous coronary intervention (from the
ARMYDA-CIN [atorvastatin for reduction of myocardial damage during
angioplasty--contrast-induced nephropathy] trial. The
American journal of cardiology 2011; 108: 1-7.
169. Ozkan
G, Ulusoy S, Orem A, Ersoz S, Alkanat M, Yucesan FB, Kaynar K, Al S. Protective
effect of the grape seed proanthocyanidin extract in a rat model of
contrast-induced nephropathy. Kidney Blood Press Res 2012; 35: 445-53.
170. O'Byrne
DJ, Devaraj S, Grundy SM, Jialal I. Comparison of the antioxidant effects of
Concord grape juice flavonoids alpha-tocopherol on markers of oxidative stress
in healthy adults. The American journal of clinical nutrition
2002; 76: 1367-74.
171. Anselm
E, Chataigneau M, Ndiaye M, Chataigneau T, Schini-Kerth VB. Grape juice causes
endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent
activation of eNOS. Cardiovascular research 2007; 73: 404-13.
172. Andreucci
M, Faga T, Pisani A, Sabbatini M, Russo D, De Sarro GB, Navarra M, Michael A.
Reversal of radiocontrast medium toxicity in human renal proximal tubular cells
by white grape juice extract. 2015; 229: 17-25
173. Pasternak
JJ, Williamson EE. Clinical pharmacology, uses, and adverse reactions of
iodinated contrast agents: a primer for the non-radiologist. Mayo
Clinic proceedings 2012; 87: 390-402.
Peer reviewer: Neslihan Toyran,
Associate Professor, Department of Physiology, Faculty of Medicine, Baskent
University, 06530 Ankara, Turkey.
Refbacks
- There are currently no refbacks.