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


Telephone: +39-339-6814750

Received: January 8, 2015                  Revised: January 30, 2015

Accepted: February 4, 2015

Published online: March 30, 2015



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:



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].



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.



The Authors have no conflicts of interest to declare.



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Peer reviewer: Neslihan Toyran, Associate Professor, Department of Physiology, Faculty of Medicine, Baskent University, 06530 Ankara, Turkey.



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