712 Reactive oxygen species (ROS) also may play an important role in contrast induced nephropathy (CIN) ROS are known to scavenge nitric oxide and cause cellular damage, but they may also mediate the[.]
712 Reactive oxygen species (ROS) also may play an important role in contrast-induced n ephropathy (CIN) ROS are known to scavenge nitric oxide and cause cellular damage, but they may also mediate the actions of vasoconstrictors thought to be of importance in the development of CIN [26] All of the abovementioned pathways may contribute to renal injury Patients with chronic kidney disease have a higher filtered load of the contrast media per nephron in addition to prolonged tubular exposure of the agent, placing them at increased risk for toxicity Overall, preexisting renal disease with decreased renal function is one of the most important risk factors for the development of CIN The extra-renal side effects of contrast media can be minor (flushing, nausea, vomiting, pruritus, headache, urticaria), intermediate (hypotension, bronchospasm), or severe (seizure, pulmonary edema, cardiac arrest, cardiac arrhythmias) The incidence of adverse reactions is very low, especially with the use of contemporary LOCM agents Minor adverse reaction rates with LOCM occur at a frequency of 0.2–0.7% of all patients [12] Serious adverse reactions with LOCM injection are extremely rare, occurring at a frequency of 0.04%.There are several case reports and case series of contrast-related side effects in patients with renal failure which include skin disorders (iododerma), vasculitis, and sialadenitis (also known as iodide mumps) [32–35] Younathan et al studied 10 patients with ESRD on chronic hemodialysis (HD) who underwent 11 procedures requiring intravascular administration of LOCM [36] The investigators did not find significant changes in blood pressure, electrocardiogram, serum osmolality, extracellular fluid volume, or body weight in these patients None of the patients required emergent dialysis after the administration of contrast A similar observation was reported by Hamani et al in eight chronic HD patients after the administration of LOCM [37] The largest group of 22 dialysis patients who received LOCM was reported by Harasawa et al The patients were followed for 5 days, and only one developed a localized urti- V R Dharnidharka and D C Rivard carial reaction [38] These reports suggest that the risk for extra-renal toxicity in ESRD patients after the administration of contrast is low and that immediate post-procedural dialysis is not necessary ialysis in the Removal of Iodinated D Contrast Media Contrast media have a molecular weight ranging from 700 to 1550 Da and their water solubility, low protein binding, and minimal intracellular penetration allow for efficient removal from blood by HD. Treatment variables such as blood flow rate, membrane surface area, membrane material, additional ultrafiltration, and dialysis time will influence contrast media clearance Currently, there are multiple published studies evaluating the removal of all classes of iodinated contrast media by HD (Table 37.1) [39–50] Comparison between these studies is difficult due to variations in contrast media molecules, time period between contrast administration and initiation of dialysis, blood flow rates, membrane type/size, time on dialysis, ultrafiltration rate, and presence of residual renal function Nevertheless, several important observations can be made from these investigations The mean reduction rate of iodine by HD increases with longer dialysis time reaching over 70% at 3 h in most studies [39, 47, 48, 50] The relationship between contrast media clearance and blood flow rate was addressed by Teraoka et al These investigators observed that when blood flow rates were set at 100, 150, and 200 mL/min, the clearance of iopromide increased to 45.35 ± 2.54, 53.88 ± 6.46, and 57.61 ± 4.72 mL/min, respectively [46] A study by Matzkies et al evaluated the clearance of iopromide using dialyzers with two different membrane materials and sizes [41] A significant increase in the plasma clearance of iodine was observed when larger dialyzers were used The clearance was also higher for the polysulfone as compared to the cuprophan dialyzers 37 Role of Radiological Assessment and Intervention in Pediatric Dialysis 713 Table 37.1 Hemodialysis removal of contrast media Study Kierdorf et al [40] Waaler et al [49] Molecular Contrast agent weight (D) Iopromide 791 Iohexol 821 Moon et al [43] Iohexol 821 Ueda et al [48] Ioversol 807 Polycarbonate Cellulose Cuprophan Cuprophan Polysulfone Cellulose Ueda et al [47] Iomeprol 777 Cellulose Johnsson et al [50] Iohexol 821 Cellulose Matzkies et al [42] Iopromide 791 Horiuchi et al [39] Matzkies et al [41] Iohexol Iopromide 821 791 Sterner et al [45] Iodixanol Iohexol Iopromide Iopromide 1550 821 791 791 Haemophan Polyamide Cellulose Cuprophan Polysulfone Low flux Schindler et al [44] Teraoka et al [46] Overall, most studies have reported that high-flux membranes were more efficient than low-flux membranes in the elimination of contrast media [42, 44] In contrast, one report by Matzkies et al studied the elimination of iopromide in chronic HD patients using low-flux (haemophan) and high-flux (polyamide) dialyzers and found a comparable difference in the clearance rates for both membranes [42] The post-dialysis rebound or redistribution of contrast media has been reported in only three studies [42, 45, 50] One study found no significant rebound when measuring the iodine concentration hour after treatment [41] However, a study by Johnsson et al reported an increase in the blood concentration of iohexol at and 24 h as compared to the immediate post-dialysis level [50] Sterner et al found similar results [24, 45] These investigators measured iodine concentrations and 45 after the conclusion of HD. When using the 45 min post-dialysis plasma level, they reported an 8–10% decrease in clearance, representing Dialyzer Hemophan Cuprammonium Contrast clearance (mL/min) 80 81 ± 15 Contrast removal 41% in 3 h 72 ± 11% in 4 h 70.4 ± 24.6 60–90% in 6 h 114–129 82.5 ± 5.1% at 4 h 81.4 ± 4.6% at 4 h 71% at 3 h 79% at 6 h 62% at 3 h 58% at 3 h 72.9% at 3 h 57–63% at 2 h 60–68% at 2 h 131.4–133.3 108 ± 1.9 110 ± 1.4 87–121 147–162 58 ± 11 69 ± 16 82 ± 2.3 57.6 64% at 4 h what they termed “hemodialysis clearance of extracellular space.” The clinical significance of the rebound effect is not known Peritoneal dialysis (PD) is relatively ineffective in removing contrast media A total of ten patients on continuous ambulatory peritoneal dialysis (CAPD) were studied after the administration of iopamidol [51] CAPD removed an average of 53.6% of the administered dose during the study period using 8 L of dialysate per day An average of 93% of the total dose was cleared when dialysis and renal clearances were combined A study by Moon et al reported three patients who received iohexol [43] Using 36–60 L of dialysate, 43–72% of the administered dose was removed over 16–18 h In another group of 14 patients with and without residual renal function, CAPD removed 75% of the administered iomeprol after a period of 4 days [52] When compared to HD, the clearance of contrast media with PD is slower However, no adverse events as a result of contrast exposure were reported in any of these studies 714 ialysis as a Strategy to Minimize D Contrast-Induced Nephropathy Post-procedural dialysis to prevent extra-renal complications in patients with ESRD does not seem to be warranted and was addressed in an above section Immediate dialysis after the administration of iodinated contrast media has been advocated for patients considered at very high risk for toxicity: ESRD patients on chronic dialysis and those with advanced chronic renal failure as a way to protect residual renal function and avoid further decreases in GFR. Several studies have shown that the administration of HD does not reduce the risk of CIN In a prospective, randomized study, Lenhnert et al evaluated the influence of HD on CIN in 30 patients with chronic renal failure [53] Both groups received pre-hydration with intravenous 0.9% saline In addition, the patients randomized to Group received HD for 3 h with a high-flux polysulfone membrane after the administration of iopentol The rate of CIN was similar for both groups (53% for Group and 40% for Group 2) despite data indicating that HD removed the iopentol effectively In a similar study, Sterner et al reported 32 patients who were randomized to receive either HD plus pre- and post-procedural hydration or hydration alone after an angiographic examination [45] HD was started within 2 h after the end of contrast administration The treatment was prescribed for 4 h using low-flux cellulose acetate or cellulose diacetate hemodialyzers The GFR was determined by iohexol clearance 1 day prior to and 1 week after the procedure There was no significant difference in the renal iohexol clearance between the groups The investigators concluded that HD was not effective in preventing CIN in patients with chronic renal failure The largest prospective, randomized study of 113 patients addressing this issue reported that the rate of CIN did not differ between the HD and standard hydration alone treatment groups [54] The same conclusion held true even for the subgroup of patients receiving a larger volume of contrast media In this study, HD was started at a V R Dharnidharka and D C Rivard median of 120 after the administration of contrast and was prescribed for a mean of 3 h using a high-flux polysulfone dialyzer The lack of protection against CIN could be the result of starting HD “late” after contrast administration given the fact that renal injury may occur rapidly A study by Frank et al evaluated the influence of simultaneous HD at the time of contrast media administration on renal function [55] Creatinine clearance was measured prior to and 8 weeks after the procedure In each of the study groups, the creatinine clearance was not different Two patients from each study arm developed ESRD requiring subsequent dialysis treatments With a small sample size of 17 patients, the study failed to demonstrate a protective effect of “early” HD on development of CIN More recently, hemofiltration has been reported by Marenzi et al as a successful strategy for the prevention of CIN [56] A total of 114 patients were randomized to receive pre-contrast hydration or hemofiltration 4–6 h prior to and 18–24 h after the angiography CIN occurred in 5% of patients in the hemofiltration group and in 50% of patients in the control group A follow-up study compared patients receiving hemofiltration after contrast administration to those receiving hemofiltration 6 h prior to and after the procedure [57] The rate of CIN was significantly less in the pre-/post-hemofiltration group as compared to the post-hemofiltration group (26% vs 3%) The mechanisms involving the protective effects of hemofiltration remain unclear, and further studies with this form of therapy are needed Negative Contrast Media The negative radiological contrast media are the gases: air, oxygen, nitric oxide (N2O), or carbon dioxide (CO2) CO2 has been used as an intravascular imaging agent for over 30 years and as an alternative to iodinated contrast agents or gadolinium in patients with advanced renal failure CO2 has certain unique properties: it is not nephrotoxic, lacks allergic potential, and is eliminated by one pass through the lungs 37 Role of Radiological Assessment and Intervention in Pediatric Dialysis Several animal studies have reported the lack of renal toxicity of CO2 Hawkins et al evaluated the effects of selective CO2 injection in the renal arteries of dogs [58] The investigators found no dose-dependent effect of CO2 on renal function or renal histology Palm et al compared the effects of CO2 with those of ioxaglate in the rat kidney [59] The pronounced decrease in medullary blood flow and PO2 observed after injection of ioxaglate was not present in the animals injected with CO2 Furthermore, a review of the published literature did not reveal any cases of CIN secondary to CO2 administration CO2 is indicated for angiography in patients with renal failure However, it is not recommended to evaluate the cerebral or coronary circulations Animal studies have suggested but failed to confirm its neurotoxicity [60, 61] However, widespread ST segment elevation, decrease in coronary flow velocity, and profound global left ventricular dysfunction were documented after administration of small doses of intracoronary carbon dioxide in swines [61] Overall, CO2 angiography is well tolerated and can be successfully used in patients with renal failure in order to avoid CIN (for a review, see Ref [62]) 715 reticuloendothelial system, eliminate ferumoxytol from circulation [65] The ability of ferumoxytol to remain largely in the intravascular space for an extended period of time has important implications in its use as a contrast agent: longer imaging studies can be attained, covering larger anatomical areas This is in contrast to GBCAs, which have a relatively short intravascular half-life and thus limited time for acquisition of imaging Ferumoxytol causes strong enhancement on T1-weighted images [66], which allows depiction of vessels while ferumoxytol remains in the intravascular space In contrast, ultrasound and MRI with GBCA can only cover limited vascular territories Various studies have shown that ferumoxytol can be used effectively as a contrast agent for ceMRA with comparable quality to GBCA, good visibility of occlusions, and the ability to image large areas of the body Figure 37.1 shows a coronal T1 image from a ferumoxytol enhanced MRI in a patient with renal failure, depicting fat saturated with ferumoxytol Figure 37.2 is a 3D reconstructed image from ferumoxytol MRI, demonstrating stenosis and internal jugular veins with collateral venous structures Ferumoxytol Ferumoxytol is a superparamagnetic iron oxide particle that is currently Food and Drug Administration (FDA) approved for intravenous iron replacement for treatment of iron deficiency anemia in patients with chronic kidney disease The FDA label additionally states that ferumoxytol alters MRI studies, and more recently, its use as a contrast agent for MRI has been studied and explored Ferumoxytol acts as a blood pool agent, as it is a relatively large molecule with a long intravascular half-life of 14–15 hours [63], compared to about 90 seconds for traditional GBCA [64] Eventually, phagocytic cells, especially macrophages of the Fig 37.1 Images from a ferumoxytol-enhanced MRI in a patient with renal failure Coronal T1 shows fat saturated with ferumoxytol 716 Fig 37.2 Three-dimensional reconstructed image from ferumoxytol MRI demonstrating stenosis and internal jugular veins with collateral venous structures Gadolinium Gadolinium is a rare earth metallic element in the lanthanide series of the periodic table, with an atomic number of 64 and molecular weight of 157.25 Da This element has the unusual property of possessing seven unpaired electrons in its outer shell, thereby making Gd an ideal “paramagnetic” substance to disturb the relaxation of surrounding water molecule protons and generate contrast in MRI [67] The GBCA are classified into four main categories based on their biochemical structure (macro-cylic or linear) and their charge (ionic or nonionic) The different properties of each category are important in order to understand their potential for toxicity as a result of liberation of free Gd from its chelate Overall, macro-cyclic chelates tend to be more stable and have lower dissociation rates Renal Handling of Gadolinium The GBCA have a molecular weight ranging from 500 to 1000 Da, are highly soluble in water, and have low binding to plasma proteins Hence, V R Dharnidharka and D C Rivard after intravenous administration, GBCA distribute into the extracellular space and rapidly equilibrate with the interstitial space There is no intracellular penetration These properties account for the small volume of distribution of GBCA (0.26–0.28 L/kg body weight) [68] Chelated Gd is freely filtered by the glomeruli, is neither secreted nor reabsorbed by the renal tubules, and is eliminated unchanged in the urine In the presence of normal renal function, GBCA clearance approximates GFR. Their mean half- life is typically under 2 h with 95% of the administered dose eliminated in the first 24 h In renal failure, the half-life can be prolonged up to 30–120 h Extra-renal elimination of GBCA is negligible with less than 3% being excreted in the stool [68, 69] Mechanisms for Toxicity of Gadolinium Though free Gd+ can be toxic, the chelated form of Gd was believed for many years to be nontoxic and generally safe Only 64 adverse reactions, mostly mild, were reported after 158,439 doses in one study [70] and only 36 adverse reactions in 21,000 patients in another study [71] Two case reports described a spurious hypocalcemia after Gd administration [72, 73] When compared to iodinated contrast media, GBCA are considered to be less nephrotoxic This is likely attributed to their lower viscosity and the need to administer significantly lower volumes Several studies in healthy patients as well as individuals with mild and moderate renal failure suggested that overall nephrotoxicity is quite low ranging from 0% to 5% [74, 75] The risk of nephrotoxicity has been reported to be much higher in patients with more advanced renal disease and after intra-arterial injection of GBCA [76–79] The exact mechanism of nephrotoxicity of GBCA is not well known However, GBCA and iodinated contrast media share the same pharmacodynamics, their nephrotoxic effects are often clinically similar, and they may cause renal damage through similar mechanisms 37 Role of Radiological Assessment and Intervention in Pediatric Dialysis More recently, Gd has been associated with a newly recognized condition called nephrogenic systemic fibrosis (NSF), which is discussed in a later section Dialysis in the Removal of Gadolinium Though GBCA clearance is delayed in renal failure, these compounds are of low molecular weight, not protein bound, and have a small volume of distribution [80–82] These properties allow for good clearance with HD. Okada et al reported the removal rate of gadopentetate in 11 patients after a 4 h HD treatment [81] The average Gd removal was 78.2% of the administered dose after the first, 95.6% after the second, 98.7% after the third, and 99.5% after the fourth treatment A similar observation was reported after administering gadodiamide to 13 patients An average of 98.9% of the administered dose was removed after three HD treatments Ueda et al evaluated the clearances of three different GBCA in an in vitro system using low-flux cellulose diacetate and higher-flux cellulose triacetate hemodializers [83] The clearance of all three GBCA was significantly higher when using the cellulose triacetate dialyzer with larger pore size The clearance of GBCA using PD is much slower Joffee et al evaluated the removal of gadodiamide in nine CAPD patients After 22 days only 69% of the administered dose had been removed [84] Hence, the clearance of GBCA by PD is inefficient and generally considered inadequate Nephrogenic Systemic Fibrosis In 2000, Cowper et al described a new condition characterized by unusual, debilitating, and frequently fatal skin induration in patients with acute or chronic renal failure [85] The induration presented as tender plaques or nodules on the limbs and trunk, differentiable from scleromyxedema by absence of facial involvement and neg- 717 ative serological features Histological characteristics included a markedly thickened dermis yet unremarkable epidermis, increased mucin deposition between widely separated collagen bundles, and absence of necrosis or ulceration The disease was initially labeled as nephrogenic fibrosing dermopathy [86] As more patients were recognized [87–93], other systemic manifestations of the disease became clear, leading to a change in the name to NSF. The exact cause of this disease was and still remains unknown However, in 2005, multiple reports emerged of a strong association with prior Gd administration in patients who developed NSF disease 4–8 weeks later [94, 95] Subsequently, Gd was detected in the skin lesions of some patients with NSF, increasing the likelihood that the association was causal [96, 97] In renal failure, free Gd can potentially be liberated into tissue Several GBCA are marketed (Table 37.2) The potential for free Gd dissociation depends on several factors, including presence or absence of ionic charge (more ionic = less likely to dissociate), chemical structure (linear more likely to dissociate than cyclic ring of chelate around Gd), and kinetic stability (half-life at pH 0.1; shorter stability more likely to dissociate) Consistent with this paradigm, the nonionic, linear chelate with a short half-life (gadodiamide) has been associated with the highest incidence of NSF. Macrocyclic GBCA result in the lowest possible gadolinium deposition in tissues The dose of GBCA administered may also play a role GBCA were approved for use in MRI at a dose of Table 37.2 FDA-approved GBCAs Commercial name Dotarem Eovist Gadavist Magnevist MultiHance Omniscan OptiMARK ProHance Generic name Gadoterate meglumine Gadoxetate disodium Gadobutrol Gadopentetate dimeglumine Gadobenate dimeglumine Gadodiamide Gadoversetamide Gadoteridol Chemical structure Macrocyclic Linear Macrocyclic Linear Linear Linear Linear Macrocyclic ... post-procedural hydration or hydration alone after an angiographic examination [45] HD was started within 2 h after the end of contrast administration The treatment was prescribed for 4 h using low-flux... with chronic renal failure The largest prospective, randomized study of 113 patients addressing this issue reported that the rate of CIN did not differ between the HD and standard hydration alone... conclusion held true even for the subgroup of patients receiving a larger volume of contrast media In this study, HD was started at a V R Dharnidharka and D C Rivard median of 120 after the administration