After the description of the Contrast-Induced Nephropathy (CIN), its epidemiology and its pathogenesis, the risk factors for the development of CIN are discussed in depth, the main ones being pre-existing renal impairment, particularly secondary to diabetic nephropathy, salt depletion and dehydration, congestive heart failure, age greater than 70 years and concurrent use of nephrotoxic drugs. Then the measures to prevent CIN are suggested, beginning with the main rules in prevention: monitoring renal function, discontinuation of potentially nephrotoxic drugs, use of either iodixanol, an iso-osmolar contrast medium or iopamidol, a low-osmolar contrast medium at the lowest dosage possible. The main procedure for prevention of CIN is an adequate hydration of the patient with either isotonic sodium chloride or sodium bicarbonate solutions. The antioxidant N-acetylcysteine may be added orally or intravenously. Other antioxidants, such as vitamin C (ascorbic acid) and vitamin E (a- or γ-tocopherol), compounds with antioxidant properties (e.g. Mesna), and β1-adrenergic receptor antagonists (e.g. Nebivolol) require further studies before deciding their use in clinical practice to prevent CIN.
 

• Contrast-Induced Nephropathy
• Contrast-Induced Acute Kidney Injury
• Acute Renal Failure
• Radiographic contrast media
• Iodinated contrast material
• Renal cells
• Renal injury

Andreucci M, Faga T, Sabbatini M, Pisani A, Russo D, et al. (2014) How to Prevent Contrast-Induced Nephropathy in Clinical Practice. J Clin Nephrol Res 1(1): 1002

CIN: Contrast-Induced Nephropathy; CI-AKI: ContrastInduced Acute Kidney Injury; CT: Computed Tomography; MDRD: Modification of Diet in Renal Disease; eGFR: Estimated Glomerular Filtration Rate; LOCM: Low-Osmolar Contrast Media; NO: Nitric Oxide; ROS: Reactive Oxygen Species; SOD: Superoxide Dismutase; MBL: Mannose-Binding Lectin; HOCM: High-Osmolar Contrast Media; IOCM: Iso-Osmolar Contrast Media; Mesna: MercaptoEthane-Sulfonate Na; MASP-2: Mbl-Associated Serine Proteases-2; MRI: Magnetic Resonance Imaging.

Contrast-Induced Nephropathy (CIN; other definition: ContrastInduced Acute Kidney Injury - CI-AKI) is an iatrogenic disease that may occur when radiographic contrast media are injected intravenously or intra-arterially to improve the visibility of internal organs and structures in X-ray based imaging techniques, such as radiography and Computed Tomography (CT), or for percutaneous coronary intervention using contrast agents. It may be so defined in any case of acute renal failure occurring (especially in patients with pre-existing renal impairment and in those with diabetes) [1] within 48-72 hrs of exposure to intravascular radiographic contrast agents that cannot be attributed to other causes. It is usually a nonoliguric acute renal failure with asymptomatic transient decline in renal function, occurring generally within 48-72 hrs of contrast administration, peaking on the third to fifth day, and returning to baseline within 10–14 days [2]. It is mirrored by an absolute (0.5 mg/dl or greater) or relative (by 25% or greater) increase in serum creatinine from baseline [3,4] or, better, by a decrease (to 30-60 mL/min - renal insufficiency – or less) in the estimated glomerular filtration rate (eGFR), i.e. the creatinine clearance calculated using the MDRD (Modification of Diet in Renal Disease) calculation [5] or the very simple Cockcroft-Gault formula [6]. The risk for CIN in outpatients with an eGFR greater than 45 ml/min per 1.73 m2 seems to be extremely low, estimated to be in the region of about 2% [7].

In 10% of patients with pre-existing renal failure undergoing coronary angiography [8] and in <1% of all patients undergoing percutaneous coronary intervention using contrast agents [9] CIN may cause a severe acute renal failure with oliguria (<400 mL/24 hrs) requiring dialysis, which is accompanied by a high mortality rate. The management of CIN is the same as that for acute renal failure due to other causes [10-12].

In order to determine the effect of Intravenous (IV) Low-Osmolar Contrast Media (LOCM) on the development of post-CT CIN, Davenport et al [13] performed a retrospective study. In 20,242 adult in patients undergoing CT examinations over a period of 10 years (10,121 untreated and 10,121 treated with IV contrast media, stratified by pre-CT stable eGFR) observed that IV LOCM is a risk factor for nephrotoxicity in patients with a stable eGFR 45 mL/min/1.73 m2 [13,14].

In another recent retrospective study involving 53,439 patients in whom serum creatinine (ranging between 2 mg/dL) was regularly checked to determine the effect of IV iodinated contrast material exposure to the incidence of CIN, McDonald et al [15] found that the incidence of CIN was not significantly different between the contrast group and control group. Thus, they suggest that intravenous iodinated contrast agents are not the cause of decreased renal function after contrast material administration.

In a systematic review and meta-analysis of controlled studies the same authors [16] examined the incidence of CIN in patients exposed to IV contrast medium compared with patients without contrast (control group); they demonstrated a similar incidence of CIN, dialysis, and death between the contrast group and control group [16].

Among all procedures utilizing contrast agents for either diagnostic or therapeutic purposes, coronary angiography and percutaneous coronary interventions are associated with the highest rates of CIN [4]. This is mainly related to (a) the intra-arterial injection, (b) the high dosage of the contrast used and (c) the type of patients who are usually in advanced age, with one or more comorbid conditions, such as advanced vascular disease, severe long-standing hypertension and diabetes [7].

The relationship of CIN to long-term adverse events (e.g. death, stroke, myocardial infarction, end-stage kidney disease, percutaneous coronary revascularization, coronary artery bypass graft surgery, cardiac arrest, etc) has been studied in 294 patients, with follow-up of at least 1 year after contrast exposure. The rate of long-term adverse events was higher in individuals with CIN [17].

Pathogenesis

The mechanisms of nephrotoxicity by contrast agents are not fully understood [18]. It can be reasonably assumed that CIN is due to many factors, including an initial increase followed by a more prolonged decrease in renal blood flow, a decrease in glomerular filtration rate, a decrease in Nitric Oxide (NO) and a severe reduction in medullary blood flow with renal ischaemia, hypoxia and direct tubular damage, formation of Reactive Oxygen Species (ROS) [19- 23], increased intratubular pressure secondary to contrast-induced diuresis, increased urinary viscosity and tubular obstruction, all frequently associated with dehydration and a decrease in the effective intravascular volume [2,10,24]. In vivo experiments in rats have demonstrated that the decrease in cortical and medullary microvascular blood flow induced by contrast media is partly accounted for by the downregulation of endogenous renal cortical and medullary NO synthesis [25]. To support the role of ROS generated in contrast media-induced vasoconstriction, the use of the Superoxide Dismutase (SOD) mimetic Tempol reduced iodixanolinduced vasoconstriction [26]. More recent work using a recombinant manganese SOD administered in vivo to rats undergoing diatrizoate treatment caused an improvement in GFR and a reduction in renal histologic damage [27].

Direct toxicity on tubular epithelial cells by contrast agents has been observed in studies of isolated tubule segments and cultured cells causing disruption of cell integrity, generation of ROS and apoptosis. Contrast agents cause cellular damage to endothelial cells, i.e. the first cells to come in contact with intravenously-injected contrast agents [2]. The contrast agents are then filtered by glomeruli and become concentrated within the tubules, thereby exposing the tubular cells to an even worse direct damage [28]. In vitro cell culture studies have shown that all types of contrast agents cause a decrease in cell viability [29-33]. The biochemical changes underlying these effects have been extended to studying changes in major intracellular signalling pathways involved in cell survival, death and inflammation [31-36] in vitro in cultured renal tubular cells [37-39]. Contrast media can cause perturbation of mitochondrial enzyme activity and apoptosis [40]. Studies in animals as well as in vitro studies suggest, in fact, that they can directly induce caspase-mediated apoptosis of renal tubular cells [41-46].

Some studies have demonstrated the crucial role played by mannose-binding lectin (MBL, a protein of the lectin pathway of the complement system) in aggravating the inflammatory response and the tissue damage during ischemia/reperfusion injury of several organs, including the kidney [47,48], that is alleviated by inhibition with C1 inhibitor, a potent MBL and lectin pathway inhibitor [49]. In experimental ischemia/reperfusion models, MBL has been found to induce tubular cell death, independent of the complement system, and contribute to endothelial dysfunction, after binding to vascular endothelial cells, by triggering a pro-inflammatory reaction [50-52]. Urinary MBL is increased after administration of contrast agents and in humans with CIN, suggesting some role of MBL in causing CIN [49,53]. In a trial assessing the importance of serum MBL for the development of CIN, the deficiency of this lectin did not influence the occurrence of CIN as defined by a serum creatinine increment; but it was associated with an increase in cystatin C after the administration of a contrast agent [54]. We have to consider that the increase of serum creatinine after contrast media is delayed, usually achieving a maximum two to five days after contrast exposure. Serum cystatin C, instead, is a more sensitive marker and has been shown to increase earlier, to peak 24 hours after contrast administration, thereby detecting even subtle changes in eGFR after acute kidney injury including CIN [55-58]. Thus, in this clinical trial, subjects with MBL deficiency were almost two-times less likely to develop an increase of ≥10% in cystatin C after administration of the contrast agent. This suggests that deficiency of MBL might attenuate some of the detrimental effects of contrast media [54].

Identification of patients at high risk for the development of CIN

The European Society of Urogenital Radiology has suggested that the real risks for CIN are represented by pre-existing renal impairment, particularly secondary to diabetic nephropathy, salt depletion and dehydration, congestive heart failure, an age greater than 70 years and concurrent use of nephrotoxic drugs [3,59]. Undoubtedly, pre-existing impairment of renal function, irrespective of cause, represents the main risk factor for CIN. The lower the eGFR, the greater is the risk of CIN. An eGFR of 60 ml/ min/1.73m2 is a reliable cutoff point for identifying patients at high risk for the development of CIN [2]. The incidence of CIN in patients with chronic renal failure ranges from 14.8 to 55% [4]. Diabetes mellitus is the second most important factor predisposing to CIN, particularly when associated with renal insufficiency [60]. At any given degree of baseline eGFR, diabetes doubles the risk of developing CIN. The incidence of CIN in diabetic patients varies from 5.7 to 29.4% [4,61,62]. he coupling of chronic kidney disease and diabetes, however, dramatically increases the risk for CIN compared with that observed for chronic kidney disease alone [63]. Another risk factor for CIN is the concomitant use of nephrotoxic drugs, such as aminoglycosides, cyclosporin A, amphotericin, cisplatin and nonsteroidal anti-inflammatory drugs [64,65] that should possibly be discontinued before radiocontrast administration [2]. The role of renin-angiotensin-aldosterone system blocking agents (angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers) in the pathophysiology of CIN is still controversial [66]. Many authors believe that these drugs should be discontinued in patients with chronic renal disease at high risk for developing CIN [67-73]. Others deny a negative influence in the incidence of CIN in stable patients with chronic renal failure [74]. KDIGO does not deem it necessary to discontinue these medications prior to contrast administration [75]. Other risk factors include: prolonged hypotension [10,76], severe dehydration, reduction of effective intravascular volume due to congestive heart failure, liver cirrhosis, or salt depletion secondary to abnormal fluid losses associated with insufficient salt intake [10,22,79-78].

CIN was first described in a patient with multiple myeloma receiving intravenous pyelography [79]. Today the incidence of CIN in patients with multiple myeloma with a normal serum creatinine is believed to be low and correlated with β2 -microglobulin levels, making the administration of contrast agents relatively safe [80].

Other important risk factors include: advanced age [4,81], anemia [82], severe congestive heart failure or compromised left ventricle systolic performance [4], sepsis [10,65,81] and renal transplant [83].

Radiographic procedures, chemical characteristics and route of administration of contrast media as risk factors for the development of CIN

Use of large doses of contrast media (e.g. in coronary angiography) and their multiple injections within 72 hrs [10,81,84] represent risks for CIN that is dose-dependent [9,85-88]. Radiographic contrast media seem to be more nephrotoxic when given intra-arterially because of the higher acute intrarenal concentration [10,89], particularly if the arterial injection is suprarenal [1, 90-96].

The contrast agents have different osmolalities (number of molecules per kilogram of water), greater than that of plasma (Table 1). Ionic High-Osmolar Contrast Media (HOCM, e.g. diatrizoate) have an osmolality of 1500 to 1800 mOsm/kg (i.e. 5–8 times the osmolality of plasma); nonionic Low-Osmolar Contrast Media (LOCM e.g. iohexol) have an osmolality of 600 to 850 mOsm/kg (i.e. 2–3 times the osmolality of plasma); nonionic Iso-Osmolar Contrast Media (IOCM e.g. iodixanol) have an osmolality of approximately 290 mOsm/kg (i.e. same osmolality as plasma). Ionicity is the characteristic of a molecule to break up into a cation and an anion, resulting in more molecules per kilogram of water, thereby increasing osmolality. Nonionic agents not having this property are less osmolar [2].

All iodinated radiocontrast media are osmotic diuretics. The higher osmolality the greater is the diuresis. This osmotic diuresis has Osmolality of contrast media compared with the osmolality of plasma. HOCM: High-Osmolar Contrast Media, the highest osmolality, 5–8 times the osmolality of plasma. LOCM: Low-Osmolar Contrast Media, an osmolality 2–3 times the osmolality of plasma. IOCM: Iso-Osmolar Contrast Media, the same osmolality as plasma.

a dehydrating effect, particularly when high doses are given as during cardiac catheterization procedures. Thus, the high incidence of CIN might be the result of this side effect explaining the beneficial effects of prophylactic hydration in preventing CIN [97].

It has been shown that the use of LOCM rather than HOCM is beneficial in preventing CIN in patients with pre-existing renal failure [98-101]. However, other studies comparing HOCM and LOCM have shown a much less than anticipated advantage for the ability of LOCM to decrease the risk of CIN, even in subjects with pre-existing renal impairment [93,97,100]. Recent studies and meta-analyses have found no significant difference in the rates of CIN between IOCM and LOCM [102-105]; only that the LOCM iohexol seems to be more nephrotoxic [98,106].

Table 1: Iodinated Contrast Media Commonly Used in Clinical Practice.

Name	mOsm/kg	Osmolality type
Metrizoate Isopaque (Conray 370)	2,100	HOCM
Diatrizoate (Hypaque 50)	1,550	HOCM
Ioxaglate (Hexabrix)	580	LOCM
Iopamidol (Isovue-370)	796	LOCM
Iohexol (Omnipaque 350)	884	LOCM
Iodixanol (Visipaque 320)	290	IOCM

 

Main rules in prevention of CIN

The first general rule of prevention is that in any patient undergoing any radiographic procedure, renal function should be monitored by measuring serum creatinine and calculating the eGFR. This is even more important in patients at high risk of CIN, in whom serum creatinine and eGFR should be checked before and once daily for 5 days after the radiographic procedure [10].

The second rule is that potentially nephrotoxic drugs should be discontinued before the contrast procedure. We refer to aminoglycosides, vancomycin, amphotericin B, metformin and nonsteroidal anti-inflammatory drugs [2]. Sometimes aminoglycosides are necessary and cannot be discontinued. For these conditions the European Renal Best Practice position [107] is “not using more than one shot of aminoglycosides for the treatment of infections… in patients with normal kidney function in steady state, aminoglycosides are administered as a single-dose daily rather than multiple-dose… monitoring aminoglycoside drug levels”. For amphotericin B, the ERBP recommends that saline loading be implemented in all patients receiving any formulation of amphotericin B [107]. The potential harm by metformin (an oral antihyperglycemic medication, used to treat type II diabetes, that stimulates intestinal production of lactic acid) is the severe lactic acidosis that may follow the occurrence of renal failure (since metformin is excreted unchanged almost entirely by the kidneys, it is retained in case of CIN); this lactic acidosis can be fatal. Thus, the drug has to be discontinued at least 12 hours before the contrast and not be resumed for a minimum of 36 hours after  the procedure, or longer if the serum creatinine has not returned to baseline [108].

The third rule is the choice of the least nephrotoxic radiocontrast agent. LOCM (e.g. iohexol) are less nephrotoxic than HOCM (e.g. diatrizoate). Moreover, IOCM (e.g. iodixanol) seem to be less nephrotoxic than LOCM [10]. In a multicenter, randomized, doubleblind comparison of iopamidol (LOCM) and iodixanol (IOCM), performed in patients with chronic kidney disease, the rate of CIN was not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus [103]. Thus, iodixanol (IOCM) and iopamidol (LOCM) appear to be contrast agents of choice to reduce risk of CIN.

The fourth rule is to use the lowest dosage possible of contrast media. High doses of contrast agents are required in percutaneous coronary intervention. For this procedure, some formulas have been suggested to calculate the dosage that is least dangerous for renal function:

(A) Cigarroa’s formula: 5 mL of contrast per kg b.w./Serum Creatinine (mg/dL) with maximum dose acceptable of 300 mL for diagnostic coronary arteriography [109].

(B) Laskey’s formula: volume of contrast to calculated creatinine clearance ratio with a cut-off point of the ratio at 3.7 for percutaneous coronary intervention; a ratio >3.7 would be associated, following contrast use, with a decrease in creatinine clearance [110]; recently the cut-off point has been placed at 2.0: below a ratio of 2.0 CIN would be a rare complication of percutaneous coronary intervention, but it would increase dramatically at a ratio of 3.0 [111,112].

(C) ratio of grams of iodine to the calculated creatinine clearance; a ratio of 1.42, or even better a ratio of 1.0, would prevent CIN [111].

Adequate hydration

The main procedure for prevention of CIN is an adequate hydration of the patient [113,114]. The old suggestion to limit fluid intake starting the day before contrast administration must be abolished and replaced by volume supplementation: e.g. 500 mL of water or soft drinks (e.g. tea) orally before and 2,500 mL for 24 hours after contrast administration in order to secure urine output of at least 1 mL/min in a non-dehydrated patient [115]. In high-risk patients adequate hydration may be obtained by IV infusion of 0.9% saline at a rate of approximately 1 mL/kg b.w.per hour, beginning 6–12 hours before the procedure and continuing for up to 12–24 hours after the radiographic examination; this may be done only if urine output is appropriate and cardiovascular condition allows it [10,113]. The rationale for volume supplementation is that hydration causes expansion of intravascular volume, suppression of renin-angiotensin cascade and consequent reduction of renal vasoconstriction and hypoperfusion. The resulting increase of diuresis will limit the duration of contrast material contact with renal tubules and consequently its toxicity on tubular epithelium [116,117].

Some clinical studies and meta-analysis have shown that sodium bicarbonate hydration is superior to sodium chloride [118-126] at least when using LOCM [127]. For patients undergoing an emergency coronary angiography or intervention the following protocol has been used: 154-mEq/L infusion of sodium bicarbonate as a bolus of 3 mL/kg b.w./hour for 1 hour before the administration of contrast, followed by 1 mL/kg/hour for 6 hours during and after the procedure [119]. The rationale for using bicarbonate infusion is explained in that any condition (such as acetazolamide administration or sodium bicarbonate infusion) that increases bicarbonate excretion decreases the acidification of urine and renal medulla. Consequently, this will reduce the production and increase the neutralization of oxygen free radicals, thereby protecting the kidney from injury by contrast agents [121,122,1285,129].

Other investigators did not find a benefit with sodium bicarbonate hydration versus sodium chloride [130-133]. Some authors found even an increased incidence of CIN with the use of intravenous sodium bicarbonate [134]. The ERBP “recommends volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions, rather than no volume expansion, in patients at increased risk for CIN” [107].

Antioxidants

Since ROS have been proved to play an important role in the renal damage caused by iodinated radiocontrast agents, the antioxidant N-acetylcysteine has been thought to 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 [10,21,135]. Shortduration pretreatment with N-acetylcysteine has been demonstrated to reduce contrast-induced cytotoxicity in human embryonic kidney cells treated with the ionic HOCM ioxithalamate, non-ionic LOCM iopromide and the IOCM iodixanol [136] and to ameliorate the ischemic renal failure in animal models [137]. Despite controversial results observed in high risk patients [134,138-147], 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 [10] 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 [139].

Other antioxidants have been suggested for use against CIN: vitamin C (ascorbic acid), vitamin E (α- or γ-tocopherol) and Mesna.

Conflicting results have been obtained with the use of ascorbic acid [136,148-150] 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 [148,149]. N-acetylcysteine (1,200 mg orally twice a day before and on the day of coronary catheterization) has been shown to be more beneficial in preventing CIN than ascorbic acid, particularly in diabetic patients with renal insufficiency undergoing coronary angiography [151]. In a recent meta-analysis, with 1536 patients who completed the trial, patients receiving ascorbic acid had a 33% less risk of developing CIN [152].

The oral administration of either 350 mg/day of α-tocopherol or 300 mg/day of γ-tocopherol (5 days prior to the coronary procedure and continued for a further 2 days post-procedure) in combination with 0.9% saline (1 mL/kg/h for 12 hours before and 12 hours after) has been demonstrated to be effective in protecting against CIN in patients with chronic kidney disease undergoing coronary procedures with Iopromide (LOCM): CIN developed in 14.9% of cases in the placebo group, but only in 4.9% and 5.9% in the α- and γ-tocopherol groups, respectively [153].

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 [154].

In a randomized controlled trial using Mesna for the prevention of CIN, the IV administration of 1600 mg Mesna versus placebo, together with intravenous hydration with 0.9% saline, resulted in the occurrence of CIN in 7 patients in the placebo group and none in the Mesna group [155]. Further studies would be necessary to confirm such a positive outcome.

Nebivolol

Nebivolol, a third-generation β1-adrenergic receptor antagonist [156,157], has been hypothesized to protect the kidney against CIN through its antioxidant and NO-mediated vasodilating action [158]. In experimental rats it has been shown to decrease medullary congestion, protein casts and tubular necrosis, systemic and renal oxidative stress, microproteinuria secondary to contrast media, and to increase the kidney nitrite level decreased by contrast media [158]. Nebivolol (5 mg/day for one week or 5 mg every 24 hours for 4 days) decreased the incidence of CIN in patients with renal dysfunction undergoing coronary angiography [159,160].

Statins

Recent studies have shown a beneficial effect of statins to prevent CIN in patients undergoing percutaneous coronary intervention [161-166]. This is not surprising, considering that hypercholesterolemia has been suggested to be a predisposing factor to CIN on the basis of a study in experimental CIN, characterized by compromised NO synthesis and enhanced ROS generation [167]. But the nephroprotective effect of statins has been attributed to their antioxidant, anti-inflammatory, and antithrombotic properties and to their vasodilator property mediated by NO, that improves renal microcirculation [168,169]. Rosuvastatin (10 mg/day for five days, two days before, three days post the procedure) reduced the risk of CIN in patients with diabetes mellitus and chronic kidney disease undergoing coronary/peripheral arterial angiography [170]. Also simvastatin had a dose-dependent nephroprotective effect in experimental rats treated with radiocontrast agents [168]. Patients on pravastatin had an even lower incidence of CIN than patients on simvastatin [171,172]. Short-term atorvastatin (40 mg/day 3 days before the procedure) and chronic atorvastatin therapy had a protective effect on renal function after coronary angiography [173]. Patients undergoing percutaneous coronary intervention were given short-term pretreatment with atorvastatin (80 mg 12 hours before intervention with another 40-mg pre-procedure, followed by longterm treatment of 40 mg/day); this prevented CIN and shortened hospital stay [174].

Steroids

It has been recently suggested that high-dose steroids (1 mg/ kg of oral prednisone, 12-24 hours before and 24 hours after the angiographic procedure) given concurrently with IV saline (1 ml/kg/ hour of 0.9% saline, 12 hours before the procedure) may protect renal tubules against either iodixanol or iohexol [175]. This is based on the fact that steroids may have a favorable impact on inflammation and on renal tubular cell apoptosis and necrosis, as observed in models of renal ischemia-reperfusion in which dexamethasone had a protective effect against injury [176].

Diuretics and Anp

Since enhanced transport activity with oxygen consumption is a principal cause of renal hypoxia and both furosemide and mannitol reduce transport activity, it has been suggested to use furosemide or mannitol (associated with saline infusion to prevent salt depletion) to protect against CIN. Several studies, however, have demonstrated either no effect in protecting against contrast media or even deleterious effect of furosemide and mannitol on renal function [177- 179]. Thus, diuretics should be avoided before contrast exposure in high-risk patients who are susceptible to volume depletion [67].

Use of Atrial Natriuretic Peptide (ANP) has also failed to protect against CIN [179,180].

Calcium Channel Blockers have been hypothesized to have protective effects against CIN. The rationale is the following: Ca2+ overload is considered to be a key factor in CIN; the increase in intracellular calcium provokes a vasoconstrictive response in intrarenal circulation and would be an important mediator of epithelial cell apoptosis and necrosis. The Na+/Ca2+ exchanger system is one of the main pathways of intracellular Ca2+ overload. It has been demonstrated that in rats the pretreatment with KB-R7943, an inhibitor of the Na+/Ca2+ exchanger system, significantly and dosedependently suppresses the increase of serum creatinine following diatrizoate administration [181]. Hence, the use of Calcium Channel Blockers has been suggested for prevention of CIN, but their use has given controversial results, sometimes protective [182,183] and sometimes with no benefit at all [177,184-186].

Other substances

Urinary adenosine is increased after contrast medium administration: thus, it has been thought that Adenosine Antagonists (theophylline, aminophylline) could have protective effects against contrast media; but their use has given controversial results. Some authors have observed beneficial effects against CIN [187-190], others have denied any beneficial results [191,192].

Dopamine and Dopamine Agonists (e.g. fenoldopam, a selective dopamine-1 receptor agonist with vasodilatory properties) have given controversial results in protecting against CIN, some positive [193-195], others negative [142,179,192,193,196,197]. On the basis of our present knowledge, it is better to avoid them, considering their adverse effects (arrhythmia with dopamine, and systemic hypotension with intravenous fenoldopam).

The plasma and urine levels of endothelin-1 are increased in diabetes and after exposure to high doses of contrast media; this has suggested a role of endothelin-1 in diabetic nephropathy and in CIN [22,198,199]. However, endothelin Receptor Blockers have been proven deleterious as a prophylactic tool against CIN [200].

Prostaglandin E1 has given some positive protective results on renal function following contrast medium injection in patients with preexisting renal impairment [201], whilst L-arginine has shown no benefit or even harm [202].

There are some experimental substances that seem promising in preventing CIN, but require further evaluation. Thus, sodium butyrate has been shown to decrease the activation of Nuclear Factor kappa B (NF-κB), thereby reducing inflammation and oxidative damage in the kidney of rats subjected to CIN [203]. Similarly, the human serum albumin–Thioredoxin (HSA–Trx) has been demonstrated to prevent CIN and renal tubular apoptosis, via its extended antioxidative action, in a rat model of ioversol-induced CIN [204]. Thioredoxin-1 – Trx - is a ubiquitous low-molecular-weight protein, produced in the human body in response to oxidative stress conditions. Finally, as already mentioned, an important role in CIN may be played by mannosebinding lectin (MBL), with observations that MBL and MASP-2 (MBL-associated serine proteases-2) were significantly upregulated in the urine samples taken 12-18 hours after administration of contrast media compared to the pre-procedural urine sample [53]. Treatment with anti-MBL monoclonal antibodies or inhibitors of MASP might be protective against contrast media in order to prevent CIN [49].

Haemodialysis or haemofiltration

It has been suggested to remove radiocontrast media by haemodialysis or haemofiltration immediately after the radiographic procedure. However, the extracorporeal removal of contrast agents did not decrease the incidence of acute renal failure in highrisk patients [205-208]. The ERBP does “not recommend using prophylactic intermittent haemodialysis or haemofiltration for the purpose of prevention of CIN” [107].

Alternative imaging method

KDIGO guidelines for Acute Kidney Injury Work Group has stated that we should “consider alternative imaging methods in patients at increased risk for CI-AKI” [75]. In fact, Magnetic Resonance Imaging (MRI) with Gadolinium-Based Contrast Agents may be an alternative imaging method. Gadolinium-Based Contrast Agents are not iodinated compounds; thus, there is no risk for CIN [209]. However, the use of Gadolinium-Based Contrast Agents may be associated with acute renal failure or nephrogenic systemic fibrosis, i.e. a rare pathology that causes fibrosis of the skin and connective tissues throughout the body involving several organs, kidney included; this occurs particularly in patients with pre-existing renal failure [210,211].

Dr. Ashour Michael is recipient of an “Assegno di Ricerca” (“Research Check”) for 2014 given by the “Magna Graecia” University of Catanzaro (Italy). M.A. has been recipient of a grant from the Italian Society of Nephrology (“S.I.N.”) for the year 2012 and for a financial research support from Amgen.

1. Katzberg RW, Newhouse JH. Intravenous contrast medium-induced nephrotoxicity: is the medical risk really as great as we have come to believe? Radiology. 2010; 256: 21-28.

2. Andreucci M, Solomon R, Tasanarong A. Side Effects of Radiographic Contrast Media: Pathogenesis, Risk Factors, and Prevention. Biomed Res Int. 2014; 2014: 741018.

3. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol. 2003; 76: 513-518.

4. Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl. 2006; : S11-15.

5. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of internal medicine. 1999; 130: 461-470.

6. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31-41.

7. Solomon R. Contrast-induced acute kidney injury: is there a risk after intravenous contrast? Clin J Am Soc Nephrol. 2008; 3: 1242-1243.

8. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. Journal of the American College of Cardiology. 1999; 33: 1756-1824.

9. McCullough PA, Wolyn R, Rocher LL, Levin RN, O’Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997; 103: 368-375.

10. Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR Am J Roentgenol. 2004; 183: 1673-1689.

11. Andreucci VE, Fuiano G, Russo D, Andreucci M. Vasomotor nephropathy in the elderly. Nephrol Dial Transplant. 1998; 13 Suppl 7: 17-24.

12. Andreucci VE, Fuiano G, Stanziale P, Andreucci M. Role of renal biopsy in the diagnosis and prognosis of acute renal failure. Kidney Int Suppl. 1998; 66: S91-95.

13. Davenport MS, Khalatbari S, Cohan RH, Dillman JR, Myles JD, Ellis JH. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material: risk stratification by using estimated glomerular filtration rate. Radiology. 2013; 268: 719-728.

14. Davenport MS, Khalatbari S, Dillman JR, Cohan RH, Caoili EM, Ellis JH. Contrast material-induced nephrotoxicity and intravenous lowosmolality iodinated contrast material. Radiology. 2013; 267: 94-105.

15. McDonald RJ, McDonald JS, Bida JP, Carter RE, Fleming CJ, Misra S, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology. 2013; 267: 106-118.

16. McDonald JS, McDonald RJ, Comin J, Williamson EE, Katzberg RW, Murad MH, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013; 267: 119-128.

17. Solomon RJ, Mehran R, Natarajan MK, Doucet S, Katholi RE, Staniloae CS, et al. Contrast-induced nephropathy and long-term adverse events: cause and effect? Clin J Am Soc Nephrol. 2009; 4: 1162-1169.

18. Andreucci M, Faga T, Pisani A, Sabbatini M, Michael A. Acute Kidney Injury by Radiographic Contrast Media: Pathogenesis and Prevention. BioMed Research Int. in press. 2014.

19. 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: 2183-2194.

20. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol. 2000; 11: 177-182.

21. Heyman SN, Rosen S, Khamaisi M, Idée JM, Rosenberger C. Reactive oxygen species and the pathogenesis of radiocontrast-induced nephropathy. Invest Radiol. 2010; 45: 188-195.

22. Detrenis S, Meschi M, Musini S, Savazzi G. Lights and shadows on the pathogenesis of contrast-induced nephropathy: state of the art. Nephrol Dial Transplant. 2005; 20: 1542-1550.

23. Pisani A, Riccio E, Andreucci M, Faga T, Michael A, Di Nuzzi A, et al. Role of reactive oxygen species (ROS) in pathogenesis of RadiocontrastInduced Nephropathy. Andreucci M, Solomon R, Tasanarong A, editors. In: “Side Effects of Radiographic Contrast Media”. Special Issue. Biomed Res Int. 2013.

24. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol. 2008; 3: 281-287.

25. Myers SI, Wang L, Liu F, Bartula LL. Iodinated contrast induced renal vasoconstriction is due in part to the downregulation of renal cortical and medullary nitric oxide synthesis. J Vasc Surg. 2006; 44: 383-391.

26. Sendeski M, Patzak A, Pallone TL, Cao C, Persson AE, Persson PB. Iodixanol, constriction of medullary descending vasa recta, and risk for contrast medium-induced nephropathy. Radiology. 2009; 251: 697-704.

27. Pisani A, Sabbatini M, Riccio E, Rossano R, Andreucci M, Capasso C, et al. Effect of a recombinant manganese superoxide dismutase on prevention of contrast-induced acute kidney injury. Clinical and experimental nephrology. 2013.

28. Sendeski MM. Pathophysiology of renal tissue damage by iodinated contrast media. Clin Exp Pharmacol Physiol. 2011; 38: 292-299.

29. Hardiek K, Katholi RE, Ramkumar V, Deitrick C. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol. 2001; 280: F61-70.

30. 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: 843-849.

31. Andreucci M, Lucisano G, Faga T, Bertucci B, Tamburrini O, Pisani A, et al. 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: 408-416.

32. Michele Andreucci, Giorgio Fuiano, Pierangela Presta, Pasquale Esposito, Teresa Faga, Vincenzo Bisesti, et al. Radio contrast media cause dephosphorylation of Akt and downstream signaling targets in human renal proximal tubular cells. Biochem Pharmacol. 2006; 72: 1334-1342.

33. Andreucci M, Faga T, Russo D, Bertucci B, Tamburrini O, Pisani A, et al. Differential activation of signaling pathways by low-osmolar and isoosmolar radiocontrast agents in human renal tubular cells. Journal of cellular biochemistry. 2014; 115: 281-289.

34. Michael A, Faga T, Pisani A, Riccio E, Bramanti P, Sabbatini M, et al. Molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast media. Andreucci M, Solomon R, Tasanarong A, editors. In: “Side Effects of Radiographic Contrast Media”. Special Issue. BioMed Research Int. 2014.

35. Andreucci M. [Contrast media and nephrotoxicity: a molecular conundrum]. G Ital Nefrol. 2011; 28: 355.

36. Sabbatini M, Santillo M, Pisani A, Paternò R, Uccello F, Serù R, et al. Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury. American journal of physiology Renal physiology. 2006; 290: F1408-1415.

37. Andreucci M, Faga T, Lucisano G, Uccello F, Pisani A, Memoli B, Sabbatini M. Mycophenolic acid inhibits the phosphorylation of NFkappaB and JNKs and causes a decrease in IL-8 release in H2O2- treated human renal proximal tubular cells. Chem Biol Interact. 2010; 185: 253-262.

38. Andreucci M, Michael A, Kramers C, Park KM, Chen A, Matthaeus T, Alessandrini A. Renal ischemia/reperfusion and ATP depletion/ repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1. Kidney Int. 2003; 64: 1189-1198.

39. Andreucci M, Fuiano G, Presta P, Lucisano G, Leone F, Fuiano L, et al. Down regulation 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: 554-561.

40. Persson PB, Hansell P, Liss P. Pathophysiology of contrast mediuminduced nephropathy. Kidney Int. 2005; 68: 14-22.

41. Singh J, Daftary A. Iodinated contrast media and their adverse reactions. J Nucl Med Technol. 2008; 36: 69-74.

42. Cunha MA, Schor N. Effects of gentamicin, lipopolysaccharide, and contrast media on immortalized proximal tubular cells. Renal failure. 2002; 24: 687-690.

43. Peer A, Averbukh Z, Berman S, Modai D, Averbukh M, Weissgarten J. Contrast media augmented apoptosis of cultured renal mesangial, tubular, epithelial, endothelial, and hepatic cells. Investigative radiology. 2003; 38: 177-182.

44. Haller C, Hizoh I. The cytotoxicity of iodinated radiocontrast agents on renal cells in vitro. Invest Radiol. 2004; 39: 149-154.

45. McCullough PA. Acute kidney injury with iodinated contrast. Crit Care Med. 2008; 36: S204-211.

46. Weisbord SD. Iodinated contrast media and the kidney. Rev Cardiovasc Med. 2008; 9 Suppl 1: S14-23.

47. Osthoff M, Katan M, Fluri F, Schuetz P, Bingisser R, Kappos L, et al. Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One. 2011; 6: e21338.

48. Trendelenburg M, Theroux P, Stebbins A, Granger C, Armstrong P, Pfisterer M. Influence of functional deficiency of complement mannose-binding lectin on outcome of patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. European heart journal. 2010; 31: 1181-1187.

49. Osthoff M, Trendelenburg M. Impact of mannose-binding lectin deficiency on radiocontrast-induced renal dysfunction. Andreucci M, Solomon R, Tasanarong A, editors. In: Side Effects of Radiographic Contrast Media. BioMed research international. 2013; 2013: 962695.

50. van der Pol P, Schlagwein N, van Gijlswijk DJ, Berger SP, Roos A, Bajema IM, et al. Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation. Am J Transplant. 2012; 12: 877-887.

51. Gorsuch WB, Chrysanthou E, Schwaeble WJ, Stahl GL. The complement system in ischemia-reperfusion injuries. Immunobiology. 2012; 217: 1026-1033.

52. de Vries B, Walter SJ, Peutz-Kootstra CJ, Wolfs TG, van Heurn LW, Buurman WA. The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury. Am J Pathol. 2004; 165: 1677-1688.

53. Wang L, Ni Z, Xie Z, Yang F, He B, Liu J, et al. Analysis of the urine proteome of human contrast-induced kidney injury using two-dimensional fluorescence differential gel electrophoresis/matrix---assisted laser desorption time-of-flight mass spectrometry/liquid chromatography mass spectrometry. American journal of nephrology. 2010; 31: 45-52.

54. Osthoff M, Piezzi V, Klima T, Christ A, Marana I, Hartwiger S, et al. Impact of mannose-binding lectin deficiency on radiocontrast-induced renal dysfunction: a post-hoc analysis of a multicenter randomized controlled trial. BMC Nephrol. 2012; 13: 99.

55. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002; 40: 221-226.

56. Herget-Rosenthal S, Marggraf G, Hüsing J, Göring F, Pietruck F, Janssen O, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004; 66: 1115-1122.

57. Rickli H, Benou K, Ammann P, Fehr T, Brunner-La Rocca HP, Petridis H,  et al. Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media. Clin Nephrol. 2004; 61: 98-102.

58. Kimmel M, Butscheid M, Brenner S, Kuhlmann U, Klotz U, Alscher DM. Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc--preliminary results. Nephrol Dial Transplant. 2008; 23: 1241- 1245.

59. Morcos SK, Thomsen HS, Webb JA. Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol. 1999; 9: 1602-1613.

60. Hardiek KJ, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications. 2008; 22: 171-177.

61. Pakfetrat M, Nikoo MH, Malekmakan L, Tabande M, Roozbeh J, Ganbar Ali RJ, et al. Comparison of risk factors for contrast-induced acute kidney injury between patients with and without diabetes. Hemodial Int. 2010; 14: 387-392.

62. Morabito S, Pistolesi V, Benedetti G, Di Roma A, Colantonio R, Mancone M, et al. Incidence of contrast-induced acute kidney injury associated with diagnostic or interventional coronary angiography. J Nephrol. 2012; 25: 1098-1107.

63. Rudnick MR, Goldfarb S, Tumlin J. Contrast-induced nephropathy: is the picture any clearer? Clin J Am Soc Nephrol. 2008; 3: 261-262.

64. Morcos SK. Contrast media-induced nephrotoxicity--questions and answers. Br J Radiol. 1998; 71: 357-365.

65. Kolonko A, Kokot F, Wiecek A. Contrast-associated nephropathy-- old clinical problem and new therapeutic perspectives. Nephrol Dial Transplant. 1998; 13: 803-806.

66. Toprak O. Conflicting and new risk factors for contrast induced nephropathy. J Urol. 2007; 178: 2277-2283.

67. Neyra JA, Shah S, Mooney R, Jacobsen G, Yee J, Novak JE. Contrastinduced acute kidney injury following coronary angiography: a cohort study of hospitalized patients with or without chronic kidney disease. Nephrol Dial Transplant. 2013; 28: 1463-1471.

68. Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS, ; Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation. 2001; 104: 1985-1991.

69. Cirit M, Toprak O, Yesil M, Bayata S, Postaci N, Pupim L, et al. Angiotensin-converting enzyme inhibitors as a risk factor for contrastinduced nephropathy. Nephron Clin Pract. 2006; 104: c20-27.

70. Kiski D, Stepper W, Brand E, Breithardt G, Reinecke H. Impact of reninangiotensin-aldosterone blockade by angiotensin-converting enzyme inhibitors or AT-1 blockers on frequency of contrast medium-induced nephropathy: a post-hoc analysis from the Dialysis-versus-Diuresis (DVD) trial. Nephrol Dial Transplant. 2010; 25: 759-764.

71. Rim MY, Ro H, Kang WC, Kim AJ, Park H, Chang JH, et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: a propensity-matched study. Am J Kidney Dis. 2012; 60: 576-582.

72. Umruddin Z, Moe K, Superdock K. ACE inhibitor or angiotensin II receptor blocker use is a risk factor for contrast-induced nephropathy. J Nephrol. 2012; 25: 776-781.

73. Onuigbo MA, Onuigbo NT. Does renin-angiotensin aldosterone system blockade exacerbate contrast-induced nephropathy in patients with chronic kidney disease? A prospective 50-month Mayo Clinic study. Renal failure. 2008; 30: 67-72.

74. Rosenstock JL, Bruno R, Kim JK, Lubarsky L, Schaller R, Panagopoulos G, DeVita MV. The effect of withdrawal of ACE inhibitors or angiotensin receptor blockers prior to coronary angiography on the incidence of contrast-induced nephropathy. Int Urol Nephrol. 2008; 40: 749-755.

75. Khwaja A. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international. 2012; 2: 1-138.

76. Barrett BJ, Parfrey PS. Prevention of nephrotoxicity induced by radiocontrast agents. N Engl J Med. 1994; 331: 1449-1450.

77. Andreucci M, Federico S, Andreucci VE. Edema and acute renal failure. Semin Nephrol. 2001; 21: 251-256.

78. Andreucci VE, Russo D, Cianciaruso B, Andreucci M. Some sodium, potassium and water changes in the elderly and their treatment. Nephrol Dial Transplant. 1996; 11: 9-17.

79. Bartels ED, Brun GC, Gammeltoft A, Gjørup PA. Acute anuria following intravenous pyelography in a patient with myelomatosis. Acta Med Scand. 1954; 150: 297-302.

80. Pahade JK, LeBedis CA, Raptopoulos VD, Avigan DE, Yam CS, Kruskal JB, et al. Incidence of contrast-induced nephropathy in patients with multiple myeloma undergoing contrast-enhanced CT. AJR Am J Roentgenol. 2011; 196: 1094-1101.

81. Cochran ST, Wong WS, Roe DJ. Predicting angiography-induced acute renal function impairment: clinical risk model. AJR Am J Roentgenol. 1983; 141: 1027-1033.

82. Nikolsky E, Mehran R, Lasic Z, Mintz GS, Lansky AJ, Na Y, et al. Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney international. 2005; 67: 706-713.

83. Ahuja TS, Niaz N, Agraharkar M. Contrast-induced nephrotoxicity in renal allograft recipients. Clin Nephrol. 2000; 54: 11-14.

84. Oliveira DB. Prophylaxis against contrast-induced nephropathy. Lancet. 1999; 353: 1638-1639.

85. Taliercio CP, Vlietstra RE, Fisher LD, Burnett JC. Risks for renal dysfunction with cardiac angiography. Ann Intern Med. 1986; 104: 501-504.

86. McCullough P. Outcomes of contrast-induced nephropathy: experience in patients undergoing cardiovascular intervention. Catheter Cardiovasc Interv. 2006; 67: 335-343.

87. Kato K, Sato N, Yamamoto T, Iwasaki YK, Tanaka K, Mizuno K. Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization. Circ J. 2008; 72: 1499-1505.

88. Nunag M, Brogan M, Garrick R. Mitigating contrast-induced acute kidney injury associated with cardiac catheterization. Cardiol Rev. 2009; 17: 263-269.

89. Dong M, Jiao Z, Liu T, Guo F, Li G. Effect of administration route on the renal safety of contrast agents: a meta-analysis of randomized controlled trials. J Nephrol. 2012; 25: 290-301.

90. Byrd L, Sherman RL. Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review. Medicine (Baltimore). 1979; 58: 270-279.

91. Harkonen S, Kjellstrand C. Contrast nephropathy. Am J Nephrol. 1981; 1: 69-77.

92. Khoury GA, Hopper JC, Varghese Z, Farrington K, Dick R, Irving JD, et al. Nephrotoxicity of ionic and non-ionic contrast material in digital vascular imaging and selective renal arteriography. Br J Radiol. 1983; 56: 631-635.

93. Moore RD, Steinberg EP, Powe NR, Brinker JA, Fishman EK, Graziano S, et al. Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial. Radiology. 1992; 182: 649-655.

94. Katzberg RW, Barrett BJ. Risk of iodinated contrast material--induced nephropathy with intravenous administration. Radiology. 2007; 243: 622-628.

95. Campbell DR, Flemming BK, Mason WF, Jackson SA, Hirsch DJ, MacDonald KJ. A comparative study of the nephrotoxicity of iohexol, iopamidol and ioxaglate in peripheral angiography. Can Assoc Radiol J. 1990; 41: 133-137.

96. Gomes AS, Baker JD, Martin-Paredero V, Dixon SM, Takiff H, Machleder HI, et al. Acute renal dysfunction after major arteriography. AJR Am J Roentgenol. 1985; 145: 1249-1253.

97. Bucher AM, De Cecco CN, Schoepf UJ, Meinel FG, Krazinski AW, Spearman JV, et al. Is contrast medium osmolality a causal factor for contrast-induced nephropathy? Andreucci M, Solomon R, Tasanarong A, editors. In: “Side Effects of Radiographic Contrast Media”. Special Issue. BioMed Research Int. 2014.

98. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ. Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and LowOsmolar Non-Ionic Contrast Media Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003; 348: 491-499.

99. Taliercio CP, Vlietstra RE, Ilstrup DM, Burnett JC, Menke KK, Stensrud SL, et al. A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography. J Am Coll Cardiol. 1991; 17: 384-390.

100. Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology. 1993; 188: 171-178.

101. Barrett BJ. Contrast nephrotoxicity. J Am Soc Nephrol. 1994; 5: 125- 137.

102. Heinrich MC, Häberle L, Müller V, Bautz W, Uder M. Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. Radiology. 2009; 250: 68-86.

103. Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS, Katholi RE, et al. Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation. 2007; 115: 3189-3196.

104. Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media: a meta-analysis of randomized controlled trials. JACC Cardiovascular interventions. 2009; 2: 645-654.

105. Bolognese L, Falsini G, Schwenke C, Grotti S, Limbruno U, Liistro F, et al. Impact of iso-osmolar versus low-osmolar contrast agents on contrast-induced nephropathy and tissue reperfusion in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (from the Contrast Media and Nephrotoxicity Following Primary Angioplasty for Acute Myocardial Infarction [CONTRAST-AMI] Trial). Am J Cardiol. 2012; 109: 67-74.

106. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol. 1999; 72: 701-703.

107. Ad-hoc working group of ERBP, Fliser D, Laville M, Covic A, Fouque D, Vanholder R, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: part 1: definitions, conservative management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012; 27: 4263-4272.

108. Thomson K. Safe use of radiographic contrast media. Aust Prescr. 2010; 33: 19-22.

109. Cigarroa RG, Lange RA, Williams RH, Hillis LD. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med. 1989; 86: 649-652.

110. Laskey WK, Jenkins C, Selzer F, Marroquin OC, Wilensky RL, Glaser R, et al. Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention. J Am Coll Cardiol. 2007; 50: 584-590.

111. Keaney JJ, Hannon CM, Murray PT. Contrast-induced acute kidney injury: how much contrast is safe? Nephrol Dial Transplant. 2013; 28: 1376-1383.

112. Gurm HS, Dixon SR, Smith DE, Share D, Lalonde T, Greenbaum A, et al. Registry. Renal function-based contrast dosing to define safe limits of radiographic contrast media in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2011; 58: 907-914.

113. Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney Int Suppl. 2006; : S16-19.

114. Balemans CE, Reichert LJ, van Schelven BI, van den Brand JA, Wetzels JF. Epidemiology of contrast material-induced nephropathy in the era of hydration. Radiology. 2012; 263: 706-713.

115. Thomsen HS. Guidelines for contrast media from the European Society of Urogenital Radiology. AJR Am J Roentgenol. 2003; 181: 1463-1471.

116. Ellis JH, Cohan RH. Prevention of contrast-induced nephropathy: an overview. Radiol Clin North Am. 2009; 47: 801-81, v.

117. Solomon R, Dauerman HL. Contrast-induced acute kidney injury. Circulation. 2010; 122: 2451-2455.

118. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004; 291: 2328- 2334.

119. Masuda M, Yamada T, Mine T, Morita T, Tamaki S, Tsukamoto Y, et al. Comparison of usefulness of sodium bicarbonate versus sodium chloride to prevent contrast-induced nephropathy in patients undergoing an emergent coronary procedure. Am J Cardiol. 2007; 100: 781-786.

120. Ozcan EE, Guneri S, Akdeniz B, Akyildiz IZ, Senaslan O, Baris N, et al. 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: 539-544.

121. Tamura A, Goto Y, Miyamoto K, Naono S, Kawano Y, Kotoku M, et al. Efficacy of single-bolus administration of sodium bicarbonate to prevent contrast-induced nephropathy in patients with mild renal insufficiency undergoing an elective coronary procedure. Am J Cardiol. 2009; 104: 921-925.

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. Am J Kidney Dis. 2009; 53: 617-627.

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. Nephrol Dial Transplant. 2010; 25: 747-758.

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: 742-748.

125. Assadi F. Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug. Pediatr Cardiol. 2006; 27: 238-242.

126. Pakfetrat M, Nikoo MH, Malekmakan L, Tabandeh M, Roozbeh J, Nasab MH, et al. 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: 629-634.

127. Jang JS, Jin HY, Seo JS, Yang TH, Kim DK, Kim TH, Urm SH. Sodium bicarbonate therapy for the prevention of contrast-induced acute kidney injury – a systematic review and meta-analysis –. Circ J. 2012; 76: 2255-2265.

128. Reddan D, Laville M, Garovic VD. Contrast-induced nephropathy and its prevention: What do we really know from evidence-based findings? J Nephrol. 2009; 22: 333-351.

129. Zoungas S, Ninomiya T, Huxley R, Cass A, Jardine M, Gallagher M, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Annals of internal medicine. 2009; 151: 631-638.

130. Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N, et al. 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- 1046.

131. 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: 1584-1592.

132. 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: 556-563.

133. Vasheghani-Farahani A, Sadigh G, Kassaian SE, Khatami SM, Fotouhi A, Razavi SA, et al. Sodium bicarbonate plus isotonic saline versus saline for prevention of contrast-induced nephropathy in patients undergoing coronary angiography: a randomized controlled trial. Am J Kidney Dis. 2009; 54: 610-618.

134. 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: 10-18.

135. Safirstein R, Andrade L, Vieira JM. Acetylcysteine and nephrotoxic effects of radiographic contrast agents--a new use for an old drug. N Engl J Med. 2000; 343: 210-212.

136. Lee HC, Sheu SH, Liu IH, Lee CC, Hsieh CC, Yen HW, et al. Impact of short-duration administration of N-acetylcysteine, probucol and ascorbic acid on contrast-induced cytotoxicity. J Nephrol. 2012; 25: 56-62.

137. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R. N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol. 1997; 272: F292-298.

138. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000; 343: 180-184.

139. 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. J Am Coll Cardiol. 2003; 41: 2114-2118.

140. Briguori C, Colombo A, Violante A, Balestrieri P, Manganelli F, Paolo Elia P, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J. 2004; 25: 206- 211.

141. Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, Keltz J, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002; 62: 2202-2207.

142. Allaqaband S, Tumuluri R, Malik AM, Gupta A, Volkert P, Shalev Y, et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv. 2002; 57: 279-283.

143. Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, et al. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J. 2004; 25: 212-218.

144. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004; 65: 1366-1374.

145. Coyle LC, Rodriguez A, Jeschke RE, Simon-Lee A, Abbott KC, Taylor AJ. Acetylcysteine In Diabetes (AID): a randomized study of acetylcysteine for the prevention of contrast nephropathy in diabetics. Am Heart J. 2006; 151: 1032.

146. Ferrario F, Barone MT, Landoni G, Genderini A, Heidemperger M, Trezzi M, et al. Piccaluga, P. Danna, and D. Scorza. Acetylcysteine and non-ionic isosmolar contrast-induced nephropathy--a randomized controlled study. Nephrology, dialysis, transplantation. 2009; 24: 3103-3107.

147. Gurm HS, Smith DE, Berwanger O, Share D, Schreiber T, Moscucci M, et al. Contemporary use and effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention. JACC Cardiovascular interventions. 2012; 5: 98-104.

148. Spargias K, Alexopoulos E, Kyrzopoulos S, Iokovis P, Greenwood DC, Manginas A, Voudris V. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation. 2004; 110: 2837-2842.

149. Alexopoulos E, Spargias K, Kyrzopoulos S, Manginas A, Pavlides G, Voudris V, et al. 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.

150. 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: 279-286.

151. Jo SH, Koo BK, Park JS, Kang HJ, Kim YJ, Kim HL, et al. 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: 576-583.

152. 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. J Am Coll Cardiol. 2013; 62: 2167- 2175.

153. Tasanarong A, Vohakiat A, Hutayanon P, Piyayotai D. New strategy of α- and γ-tocopherol to prevent contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures. Nephrology, dialysis, transplantation. 2013; 28: 337- 344.

154. 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- 2340.

155. 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: 302-308.

156. Veverka A, Nuzum DS, Jolly JL. Nebivolol: a third-generation betaadrenergic blocker. Ann Pharmacother. 2006; 40: 1353-1360.

157. Sule SS, Frishman W. Nebivolol: new therapy update. Cardiol Rev. 2006; 14: 259-264.

158. Toprak O, Cirit M, Tanrisev M, Yazici C, Canoz O, Sipahioglu M, et al. Preventive effect of nebivolol on contrast-induced nephropathy in rats. Nephrol Dial Transplant. 2008; 23: 853-859.

159. Avci E, YeÅŸil 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: 613-617.

160. Günebakmaz O, Kaya MG, Koc F, Akpek M, Kasapkara A, Inanc MT, et al. Does nebivolol prevent contrast-induced nephropathy in humans? Clin Cardiol. 2012; 35: 250-254.

161. Khanal S, Attallah N, Smith DE, Kline-Rogers E, Share D, O’Donnell MJ, et al. Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med. 2005; 118: 843- 849.

162. Patti G, Nusca A, Chello M, Pasceri V, D’Ambrosio A, Vetrovec GW, et al. Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2008; 101: 279-285.

163. Leoncini M, Toso A, Maioli M, Tropeano F, Bellandi F. Statin treatment before percutaneous cononary intervention. J Thorac Dis. 2013; 5: 335-342.

164. Zhang BC, Li WM, Xu YW. High-dose statin pretreatment for the prevention of contrast-induced nephropathy: a meta-analysis. Can J Cardiol. 2011; 27: 851-858.

165. Andreucci M. [Statins in CIN: a problem at least partly solved?]. G Ital Nefrol. 2013; 30.

166. Sabbatini M, Pisani A, Uccello F, Serio V, Serù R, Paternò R, et al. Atorvastatin improves the course of ischemic acute renal failure in aging rats. J Am Soc Nephrol. 2004; 15: 901-909.

167. Yang D, Lin S, Yang D, Wei L, Shang W. Effects of short- and long-term hypercholesterolemia on contrast-induced acute kidney injury. Am J Nephrol. 2012; 35: 80-89.

168. Al-Otaibi KE, Al Elaiwi AM, Tariq M, Al-Asmari AK. Simvastatin attenuates contrast-induced nephropathy through modulation of oxidative stress, proinflammatory myeloperoxidase, and nitric oxide. Oxid Med Cell Longev. 2012; 2012: 831748.

169. Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation. 2012; 126: 3008-3016.

170. Han Y, Zhu G, Han L, Hou F, Huang W, Liu H, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol. 2014; 63: 62-70.

171. Yoshida S, Kamihata H, Nakamura S, Senoo T, Manabe K, Motohiro M, et al. Prevention of contrast-induced nephropathy by chronic pravastatin treatment in patients with cardiovascular disease and renal insufficiency. J Cardiol. 2009; 54: 192-198.

172. Muñoz MA, Maxwell PR, Green K, Hughes DW, Talbert RL. Pravastatin versus simvastatin for prevention of contrast-induced nephropathy. J Cardiovasc Pharmacol Ther. 2011; 16: 376-379.

173. Acikel S, Muderrisoglu H, Yildirir A, Aydinalp A, Sade E, Bayraktar N, et al. Prevention of contrast-induced impairment of renal function by short-term or long-term statin therapy in patients undergoing elective coronary angiography. Blood Coagul Fibrinolysis. 2010; 21: 750-757.

174. Patti G, Ricottini E, Nusca A, Colonna G, Pasceri V, D’Ambrosio A, et al. 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. Am J Cardiol. 2011; 108: 1-7.

175. Ribichini F, Gambaro A, Pighi M, Pesarini G, Ferraro PM, Zuppi C, et al. Effects of prednisone on biomarkers of tubular damage induced by radiocontrast in interventional cardiology. J Nephrol. 2013; 26: 586-593.

176. Kumar S, Allen DA, Kieswich JE, Patel NS, Harwood S, Mazzon E, et al. Dexamethasone ameliorates renal ischemia-reperfusion injury. J Am Soc Nephrol. 2009; 20: 2412-2425.

177. 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. N Engl J Med. 1994; 331: 1416-1420.

178. Weinstein JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron. 1992; 62: 413- 415.

179. Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int. 1994; 45: 259-265.

180. Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, Weisberg LS. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis. 1998; 31: 674-680.

181. Yang D, Yang D, Jia R, Tan J. Na+/Ca2+ exchange inhibitor, KBR7943, attenuates contrast-induced acute kidney injury. J Nephrol. 2013; 26: 877-885.

182. Neumayer HH, Junge W, Küfner A, Wenning A. Prevention of radiocontrast-media-induced nephrotoxicity by the calcium channel blocker nitrendipine: a prospective randomised clinical trial. Nephrol Dial Transplant. 1989; 4: 1030-1036.

183. Russo D, Testa A, Della Volpe L, Sansone G. Randomised prospective study on renal effects of two different contrast media in humans: protective role of a calcium channel blocker. Nephron. 1990; 55: 254-257.

184. Khoury Z, Schlicht JR, Como J, Karschner JK, Shapiro AP, Mook WJ, et al. The effect of prophylactic nifedipine on renal function in patients administered contrast media. Pharmacotherapy. 1995; 15: 59-65.

185. Spångberg-Viklund B, Berglund J, Nikonoff T, Nyberg P, Skau T, Larsson R. Does prophylactic treatment with felodipine, a calcium antagonist, prevent low-osmolar contrast-induced renal dysfunction  in hydrated diabetic and nondiabetic patients with normal or moderately reduced renal function? Scand J Urol Nephrol. 1996; 30: 63-68.

186. Caiazza A, Russo L, Sabbatini M, Russo D. Hemodynamic and Tubular Changes Induced by Contrast Media. Andreucci M, Solomon R, Tasanarong A, editors. In: “Side Effects of Radiographic Contrast Media”. BioMed Research Int. 2014.

187. Erley CM, Duda SH, Schlepckow S, Koehler J, Huppert PE, Strohmaier WL, et al. Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney international. 1994; 45: 1425-1431.

188. Katholi RE, Taylor GJ, McCann WP, Woods WT Jr, Womack KA, McCoy CD, et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology. 1995; 195: 17-22.

189. Erley CM, Duda SH, Rehfuss D, Scholtes B, Bock J, Muller C, et al. Prevention of radiocontrast-media-induced nephropathy in patients with pre-existing renal insufficiency by hydration in combination with the adenosine antagonist theophylline. Nephrology, dialysis, transplantation. 1999; 14: 1146-1149.

190. Huber W, Ilgmann K, Page M, Hennig M, Schweigart U, Jeschke B, et al. Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology. 2002; 223: 772-779.

191. Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, et al. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol. 1999; 83: 260-263.

192. Shammas NW, Kapalis MJ, Harris M, McKinney D, Coyne EP. Aminophylline does not protect against radiocontrast nephropathy in patients undergoing percutaneous angiographic procedures. J Invasive Cardiol. 2001; 13: 738-740.

193. Hans SS, Hans BA, Dhillon R, Dmuchowski C, Glover J. Effect of dopamine on renal function after arteriography in patients with pre-existing renal insufficiency. Am Surg. 1998; 64: 432-436.

194. Chamsuddin AA, Kowalik KJ, Bjarnason H, Dietz CA, Rosenberg MS, Gomes MD, et al Using a dopamine type 1A receptor agonist in high-risk patients to ameliorate contrast-associated nephropathy. AJR Am J Roentgenol. 2002; 179: 591-596.

195. Kini AS, Mitre CA, Kamran M, Suleman J, Kim M, Duffy ME, et al. Changing trends in incidence and predictors of radiographic contrast nephropathy after percutaneous coronary intervention with use of fenoldopam. Am J Cardiol. 2002; 89: 999-1002.

196. Gare M, Haviv YS, Ben-Yehuda A, Rubinger D, Bdolah-Abram T, Fuchs S, et al. The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography. J Am Coll Cardiol. 1999; 34: 1682-1688.

197. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA. 2003; 290: 2284- 2291.

198. Khamaisi M, Raz I, Shilo V, Shina A, Rosenberger C, Dahan R, et al. Diabetes and radiocontrast media increase endothelin converting enzyme-1 in the kidney. Kidney international. 2008; 74: 91-100.

199. Russo D, Minutolo R, Cianciaruso B, Memoli B, Conte G, De Nicola L. Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol. 1995; 6: 1451- 1458.

200. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int. 2000; 57: 1675-1680.

201. Koch JA, Plum J, Grabensee B, Mödder U. Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? PGE1 Study Group. Nephrol Dial Transplant. 2000; 15: 43-49.

202. Miller HI, Dascalu A, Rassin TA, Wollman Y, Chernichowsky T, Iaina A. Effects of an acute dose of L-arginine during coronary angiography in patients with chronic renal failure: a randomized, parallel, doubleblind clinical trial. American journal of nephrology. 2003; 23: 91-95.

203. Machado RA, Constantino Lde S, Tomasi CD, Rojas HA, Vuolo FS, Vitto MF, et al. Sodium butyrate decreases the activation of NFkappaB reducing inflammation and oxidative damage in the kidney of rats subjected to contrast-induced nephropathy. Nephrol Dial Transplant. 2012; 27: 3136-3140.

204. Kodama A, Watanabe H, Tanaka R, Tanaka H, Chuang VT, Miyamoto Y, et al. A human serum albumin-thioredoxin fusion protein prevents experimental contrast-induced nephropathy. Kidney international. 2013; 83: 446-454.

205. Lehnert T, Keller E, Gondolf K, Schäffner T, Pavenstädt H, Schollmeyer P. Effect of haemodialysis after contrast medium administration in patients with renal insufficiency. Nephrol Dial Transplant. 1998; 13: 358-362.

206. Schindler R, Stahl C, Venz S, Ludat K, Krause W, Frei U. Removal of contrast media by different extracorporeal treatments. Nephrol Dial Transplant. 2001; 16: 1471-1474.

207. Vogt B, Ferrari P, Schönholzer C, Marti HP, Mohaupt M, Wiederkehr M, et al. Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med. 2001; 111: 692-698.

208. Vincent L. M. Esnault. Radiocontrast media-induced nephrotoxicity in patients with renal failure: rationale for a new double-blind, prospective, randomized trial testing calcium channel antagonists. Nephrology, dialysis, transplantation. 2002; 17: 1362-1364.

209. Wood SP. Contrast-induced nephropathy in critical care. Crit Care Nurse. 2012; 32: 15-23.

210. Kallen AJ, Jhung MA, Cheng S, Hess T, Turabelidze G, Abramova L, et al. Gadolinium-containing magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a case-control study. Am J Kidney Dis. 2008; 51: 966-975.

211. Bahrami S, Raman SS, Sauk S, Salehmoghaddam S, Villablanca JP, Finn JP, et al. Ten-year experience with nephrogenic systemic fibrosis: case-control analysis of risk factors. J Comput Assist Tomogr. 2009; 33: 819-823.