**5. Pathophysiology**

No definitive causative has been defined as regards the pathogenesis of CIN in the literature. The most accepted theory for the development of CIN following contrast administration relies upon the vasoconstriction of the vessels in the renal medulla leading to reduced oxygen delivery [40]. Reduced oxygen delivery and prolonged vasoconstriction leads to enhanced production of oxygen-free radicals like hydrogen peroxide and superoxide leading to increased damage [41]. Other suggested causes of this condition are elevated blood viscosity, reperfusion injury, direct toxic damage to the cells, and the release of dopamine, angiotensin II, and vasopressin. These factors induce further vasoconstriction and damage the renal function [42]. The use of supportive therapy in critically ill patients, for instance, the mechanical ventilation and inotropic drugs, and the variable health risks this group of patients have as anemia and sepsis have been shown to increase additional kidney damage resulting from vasoconstriction and hypoxia [43].

#### **5.1 Regional hypoxia as a cause of contrast-induced nephropathy (CIN)**

Renal perfusion is very high in the cortex. The medullary portions are maintained at the border of hypoxia such that pO2 levels can be as low as 20 mmHg [44]. This is the price for maintaining the countercurrent mechanism used for the control of urine excretion. A vulnerable kidney region is the deeper part of the outer medulla, an area far from the vasa recta which supply the renal medulla with blood. It is there where the thick ascending limbs of the loop of Henle encounter hypoxic damage [45]. The cause for the vulnerability of the outer medullary portion of the nephron is the relatively higher oxygen needs due to salt reabsorption. The addition of contrast media to the medium augments the hypoxic injury imposed upon this region by increasing the renal vascular resistance, as seen in the rat model [46]. A second factor that has been postulated to mediate CIN is

**125**

*Contrast-Induced Nephropathy*

limb is the Na-K<sup>+</sup>

consumption.

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

an elevated oxygen demand due to an enhanced workload in the tubular cells. First, there is a temporary increase in GFR that follows giving contrast media [47], and second, osmotic diuresis may reduce the para-cellular absorption of the proximal tubular cells, causing a greater load of NaCl that has to be absorbed in the distal tubules. Liss et al. [48] have shown that contrast media can enhance medullary blood flow to the kidney, although pO2 decreases, which is supported also by a study of Heyman et al. [49]. These two studies suggest that an increased oxygen demand has taken place following contrast media injection. Local kidney hypoxia can be augmented by the systemic effects of some contrast media, such as transiently diminished cardiac output [50] and abnormal pulmonary ventilationperfusion relationship [51]. Also, the amount of oxygen delivered to the peripheral tissues might be impaired, since contrast media can increase oxygen affinity of hemoglobin [52]. If renal outer medullary hypoxia causes CIN, the blockade of the transporters in this portion of the nephron must have helpful effects on its prevention. The major part of the transport that occurs in the medullary thick ascending


furosemide. Blocking this transport would significantly decrease the local oxygen

Renal blood flow and intrarenal microcirculation are markedly altered by contrast medium (CM) [53]. The extent and distribution of renal hemodynamic changes depends on the species investigated as well as on the type, volume, and rate of contrast administration. Moreover, renal hemodynamic effects of CM gravely depend on the hydration state and on additional predisposing factors that may have an effect on the renal circulation and the tone of the renal vasculature, such as chronic renal disease, diabetes mellitus, senility, and inflammation. In an early study in dogs subjected to a high-osmolar CM, total renal blood flow was transiently enhanced for 5–15 min, followed by a decline by 25% below baseline, reaching beyond a couple of hours [54]. In healthy humans, renal blood flow fell 8% over 30 min after the intravenous administration of conventional doses of CM [53]. On the contrary, in patients with chronic kidney disease undergoing coronary angiography, a transient short augmentation of renal blood flow was followed by a

Investigations performed in vitro on cell lines are used to assess the renal tubular cell function or damage. A porcine cell line of renal proximal tubules, LLC-PK1, was used by Hardiek et al. [55] to investigate the occurrence of CIN. An effect on apoptosis was not elucidated, even though proliferation was impaired. Diminished proliferation will have a hazardous effect on renal function with a delay of hours to days, which may help in explaining the course of CIN. Independent of the contrast media used, tubular cell damage can occur. A more specific distortion of proximal tubular function seems to be a perturbation of mitochondrial enzymatic activity and mitochondrial membrane potential [56]. The degree of mitochondrial enzymatic activity impairment depends mainly on two features of the contrast media: the ionic nature as well as the molecular structure. Remarkably, low-osmolar contrast media had the least observed effects, followed by the iso-osmolar contrast media. Ionic compounds showed the most deleterious effects [56]. In the distal tubule, contrast media may trigger apoptotic effects in the cells, as depicted in the

**5.2 Radiocontrast-mediated changes in renal blood supply**

dramatic 40% decline, lasting for more than 3 h [54].

Madin-Darby canine kidney (MDCK) cell line model [57].

**5.3 Cytotoxic effects on renal tubular cells**

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

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

Most side effects attributable to contrast media are linked to its hypertonicity. Currently, four main types of contrast media are used in practice today, including nonionic low-osmolar, ionic low-osmolar, nonionic iso-osmolar, and ionic high-osmolar contrast media. In a large study which compared the nonionic lowosmolality agent iohexol to the ionic high-osmolality agent meglumine/sodium diatrizoate in patients with preexisting renal impairment undergoing angiography, patients with renal impairment who received diatrizoate were 3.3 times more liable to develop CIN in comparison with those receiving iohexol [38]. NEPHRIC trial is a randomized, prospective study that made a comparison between the nonionic iso-osmolar CM iodixanol with the nonionic low-osmolar CM iohexol in 129 patients with renal impairment and diabetes undergoing coronary or aortofemoral angiography. The incidence of CIN was 3% in the iodixanol group and 26% in the iohexol group (p = 0.002) [39]. In one other randomized study, the incidence of CIN provoked by iodixanol and iohexol was compared in 124 patients with basal creatinine level >1.7 mg/dl. The incidence of CIN was 3.7% in iodixanol group and 10% in iohexol group (p > 0.05) [17]. In addition, CM are classified as ionic and nonionic. A randomized trial of 1196 patients performing coronary angiography showed that nonionic CM lowered the incidence of CIN in patients with preexisting renal impairment [38]. In high-risk patients, it is better to avoid the use the high-

No definitive causative has been defined as regards the pathogenesis of CIN in the literature. The most accepted theory for the development of CIN following contrast administration relies upon the vasoconstriction of the vessels in the renal medulla leading to reduced oxygen delivery [40]. Reduced oxygen delivery and prolonged vasoconstriction leads to enhanced production of oxygen-free radicals like hydrogen peroxide and superoxide leading to increased damage [41]. Other suggested causes of this condition are elevated blood viscosity, reperfusion injury, direct toxic damage to the cells, and the release of dopamine, angiotensin II, and vasopressin. These factors induce further vasoconstriction and damage the renal function [42]. The use of supportive therapy in critically ill patients, for instance, the mechanical ventilation and inotropic drugs, and the variable health risks this group of patients have as anemia and sepsis have been shown to increase additional

kidney damage resulting from vasoconstriction and hypoxia [43].

**5.1 Regional hypoxia as a cause of contrast-induced nephropathy (CIN)**

Renal perfusion is very high in the cortex. The medullary portions are maintained at the border of hypoxia such that pO2 levels can be as low as 20 mmHg [44]. This is the price for maintaining the countercurrent mechanism used for the control of urine excretion. A vulnerable kidney region is the deeper part of the outer medulla, an area far from the vasa recta which supply the renal medulla with blood. It is there where the thick ascending limbs of the loop of Henle encounter hypoxic damage [45]. The cause for the vulnerability of the outer medullary portion of the nephron is the relatively higher oxygen needs due to salt reabsorption. The addition of contrast media to the medium augments the hypoxic injury imposed upon this region by increasing the renal vascular resistance, as seen in the rat model [46]. A second factor that has been postulated to mediate CIN is

*4.14.2 High-osmolar and ionic CM*

osmolar and ionic CM to lower the risk of CIN.

**5. Pathophysiology**

**124**

an elevated oxygen demand due to an enhanced workload in the tubular cells. First, there is a temporary increase in GFR that follows giving contrast media [47], and second, osmotic diuresis may reduce the para-cellular absorption of the proximal tubular cells, causing a greater load of NaCl that has to be absorbed in the distal tubules. Liss et al. [48] have shown that contrast media can enhance medullary blood flow to the kidney, although pO2 decreases, which is supported also by a study of Heyman et al. [49]. These two studies suggest that an increased oxygen demand has taken place following contrast media injection. Local kidney hypoxia can be augmented by the systemic effects of some contrast media, such as transiently diminished cardiac output [50] and abnormal pulmonary ventilationperfusion relationship [51]. Also, the amount of oxygen delivered to the peripheral tissues might be impaired, since contrast media can increase oxygen affinity of hemoglobin [52]. If renal outer medullary hypoxia causes CIN, the blockade of the transporters in this portion of the nephron must have helpful effects on its prevention. The major part of the transport that occurs in the medullary thick ascending limb is the Na-K<sup>+</sup> -2Cl<sup>−</sup> cotransporter, which, as mentioned above, is blocked by furosemide. Blocking this transport would significantly decrease the local oxygen consumption.
