*6.1.3 Sodium bicarbonate-based hydration*

The acidic PH promotes free radical production (which is found in tubular urine) [71], while elevated pH of normal extracellular fluid inhibits it [72, 73]. Since CM administration escalates the oxidative stress and increases the generation of free radicals and reactive oxygen species (ROS), alkalinizing renal tubular fluid with bicarbonate appears to be a logical strategy to protect against renal injury [74]. As a result of active reabsorption, bicarbonate concentration in the renal tubules lowers (to about 6mEq/L), and the tubular fluid pH is approximately 6.5 near the end of the proximal tubule in the renal medulla [75]. In the descending loop of Henle, water and chloride are passively reabsorbed. This elevates urine pH to ~7.4 at the tip of the papilla, and this part is spared from contrast nephropathy [76], which suggests that higher pH is protective. Also important is the observation that outer medulla is the most susceptible to CIN [62] and has acidic pH [72] that promotes activity of ROS. Superoxide, a ROS generated by ischemia, might react with medullary NO to produce the potent oxidant peroxynitrite [73]. At physiologic concentrations, bicarbonate scavenges peroxynitrite and other ROSs produced from NO [74]. Thus, several oxidant mechanisms of renal injury might be avoided using sodium bicarbonate. The useful effect of higher proximal tubular pH is approved by a report that acetazolamide, a carbonic-anhydrase inhibitor which blocks proximal tubular bicarbonate reabsorption, is protective in contrast-induced renal failure [77]. Merten et al. reported first study on the use of sodium bicarbonate in humans as a nephron-protective agent [78]. Patients received 154mEq/l of either NaCl (in 5% dextrose H2O) or sodium bicarbonate (in dextrose H2O), as a bolus of 3mL/kg/h for 1h before iopamidol contrast, followed by an infusion of 1mL/kg/h for 6h after the procedure. CIN occurred in 8 patients (13.6%) infused with NaCl but in only 1 (1.7%) of those receiving sodium bicarbonate (p = 0.02). Afterwards, many RCTs have compared the efficacy of sodium bicarbonate with saline hydration regarding the prophylaxis against CIN. These have been reviewed in multiple meta-analysis [79–82], which concluded that sodium bicarbonate-based saline hydration is more efficacious to saline hydration only.

#### *6.1.4 Pharmacological prophylaxis*

Various drugs have been assessed as prophylactic nephroprotective agents against contrast-induced acute kidney injury (CI-AKI) such as N-acetylcysteine (NAC) [36, 83], statins [84, 85], ascorbic acid [76, 86], and theophylline [87]. However, only statins have been approved for the prevention against the occurrence of CIN. Currently, the CM safety committee recommends the withdrawal of nephrotoxic drugs before CM administration [85].

#### *6.1.5 N-Acetylcysteine (NAC)*

NAC gives protection against CIN by improving the body's antioxidant abilities [88]. In vitro, NAC does this efficiently by scavenging hypochlorous acid as well as reacting with hydroxyl radicals [89]. In vivo due to its extensive degradation, it is likely that any antioxidant effect it exerts would be indirect, most probably by inducing glutathione synthesis. Different studies have suggested that NAC guards against glutathione depletion [90, 91] and elevates renal glutathione levels [92]; the latter has been demonstrated to result in the reduction of renal injury in ischemia reperfusion models [93, 94] and recently in CIN [95, 96]. Glutathione cannot enter the cell; instead, it must be formed inside the cell from glycine, glutamate, and cysteine [97]. Cysteine offers the active HS group which is crucial for the glutathione synthesis and thus is the rate-limiting factor in this process. NAC after deacylation produces cysteine that passes to the renal cells and serves as a precursor for glutathione synthesis. It can also produce vasodilator effects [98]. By ameliorating contrast-induced vasoconstriction, NAC can produce its nephron-protective role [99]. Increase in the medullary blood flow with NAC has also been demonstrated [100, 101]. The first clinical use of NAC for CIN was reported by Tepel et al. [83]. Eighty-three patients who had chronic renal impairment were randomly planned either to take oral NAC (600mg twice daily) and 0.45% saline intravenously, before and after administration of the CM, or to receive placebo and saline. NAC-receiving patients had lower incidence of CIN. Since then numerous studies have assessed the role of NAC against CIN. Those studies have been done mainly in patients undergoing coronary angiography [102]. Some 17 meta-analyses have been published as regards this subject [76, 86, 87, 103–116], 10 that approve its use (most of which were published early on). Most of these meta-analyses reported vast heterogeneity that makes it difficult to make clinical treatment recommendations relying on the provided data. Recently, results of the largest multicenter RCT of 2308 patients called "Acetylcysteine for Contrast-Induced Nephropathy Trial" (ACT) have been published [36]. It randomized patients in 46 centers in Brazil, to take 1200mg of oral NAC or placebo twice daily for 2 doses before and after the procedure. Intravenous hydration with normal saline, 1mL/kg/h, from 6–12h before to 6–12h after angiography, was strongly recommended. NAC was not able to significantly reduce the incidence of CIN (12.7% in the NAC group and 12.7% in the control group, p = 0.97) [117].

#### *6.1.6 Ascorbic acid*

Ascorbic acid serves as an antioxidant [118]. It does this via reacting with most biologically relevant free radicals and oxidants such as superoxide ions and hydroxyl ion [119]. It donates an electron to devastating oxidizing radicals [120]; this oneelectron oxidation leads to the formation of AHˉ the ascorbyl radical also called semidehydroascorbic acid [121]. Consequently, the reactive free radical is reduced [122]. Ascorbic acid has been reported to result in vasodilatation in coronary [123] and brachial arteries [124]. Thus, vitamin C can have favorable effects on vascular dilatation, through its antioxidant actions on nitric oxide, but these findings are not consistent [125]. Through which pathway vitamin C may offer nephron protection against CIN is still currently uninvestigated. The first clinical use of ascorbic

**129**

*6.2.2 Theophylline*

*Contrast-Induced Nephropathy*

*DOI: http://dx.doi.org/10.5772/intechopen.90457*

by the contrast media safety committee.

statins are warranted [129].

*6.2.1 High-dose versus low-dose statins*

**6.2 Statins**

acid for CIN prevention was reported by Spargias and his colleagues [116]. Two hundred and thirty-one patients were summoned and randomized to obtain either 3g of ascorbic acid supplied in chewable tablets or placebo at least 2h prior to the beginning of the required procedure. This was followed by 2g of ascorbic acid or placebo the night and the morning post-procedure. Intravenous hydration with normal saline at a rate of 50–125mL/h was started in every patient till at least 6 h post-procedure. Incidence of CIN was less in ascorbic acid group (9%) and 20% in control group (p = 0.02). A considerable change in the antioxidant state was noticed in the group treated with ascorbic acid. Since then various RCTs have been performed [126, 127]. Pooled analysis of these trials assumed that patients who receive ascorbic acid have 33% less risk of CIN in comparison with patients receiving placebo or alternative pharmacological therapy (RR: 0.67 (95% CI: 0.46–0.96), p = 0.03) [100]. This indicates that ascorbic acid provides effective nephron protection in the face of CIN and may form a part of efficient prophylactic pharmacological regimens. However, the utilization of ascorbic acid has not yet been recommended

Statins maintain nitric oxide formation, lower oxidative stress, and beneficially affect the endothelial function [101]. In one retrospective study of more than 1,000 patients with renal impairment undergoing coronary angiography, the risk of CIN was markedly decreased in patients who are receiving a statin before the procedure [128]. Another study of more than 29,000 patient recorded in a percutaneous cardiac intervention registry demonstrated that patients who received statins before the procedure had both a lower CIN incidence (p < 0.0001) and nephropathy that required dialysis (p < 0.03) [181]. Further studies looking into the benefit from

High-dose statin therapy may be theoretically more efficacious regarding CIN prevention as a result of acute suppression of inflammatory chemokines [130]. Xie and his colleagues investigated the potency of high-dose statins (simvastatin 80mg, atorvastatin 40 and 80 mg) compared with low-dose statins (simvastatin 20 mg, atorvastatin 10 and 20mg) and revealed that high-dose statins lowered the incidence of CIN [131]. These results were backed up by a recent meta-analysis which showed that high-dose statins (atorvastatin 80 mg, simvastatin 80 mg) in comparison with low-dose statins (atorvastatin 10 and 20 mg, simvastatin 20 mg) in patients having acute coronary syndromes resulted in a relative risk ratio for CIN of 0.46 (4.5 vs 10.2%, p = 0.004); however, it was not of considerable significance among patients performing elective procedures [132]. However, high-dose statins

are guideline recommended medications to lower the risk of CIN.

Adenosine has been implicated to be a responsible factor for mediating CM-enhanced renal vasoconstriction [133–135]: hence the use of adenosine antagonists appears logical [136]. Theophylline and aminophylline have been often used to measure their efficacy as adenosine receptor antagonists in guarding against contrast-induced acute kidney injury (CI-AKI). Various randomized trials have used theophylline [20, 137, 138]. A meta-analysis of those studies guided to the fact that theophylline considerably lowers the risk of CIN (RR: 0.48; 95% CI: 0.26–0.89;

#### *Contrast-Induced Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.90457*

acid for CIN prevention was reported by Spargias and his colleagues [116]. Two hundred and thirty-one patients were summoned and randomized to obtain either 3g of ascorbic acid supplied in chewable tablets or placebo at least 2h prior to the beginning of the required procedure. This was followed by 2g of ascorbic acid or placebo the night and the morning post-procedure. Intravenous hydration with normal saline at a rate of 50–125mL/h was started in every patient till at least 6 h post-procedure. Incidence of CIN was less in ascorbic acid group (9%) and 20% in control group (p = 0.02). A considerable change in the antioxidant state was noticed in the group treated with ascorbic acid. Since then various RCTs have been performed [126, 127]. Pooled analysis of these trials assumed that patients who receive ascorbic acid have 33% less risk of CIN in comparison with patients receiving placebo or alternative pharmacological therapy (RR: 0.67 (95% CI: 0.46–0.96), p = 0.03) [100]. This indicates that ascorbic acid provides effective nephron protection in the face of CIN and may form a part of efficient prophylactic pharmacological regimens. However, the utilization of ascorbic acid has not yet been recommended by the contrast media safety committee.
