Imaging Patients with Kidney Disease—Weighing the Risks and Benefits


This is primarily driven by dose, distribution half-life (T1/2), and elimination T1/2. The majority of GBCAs rapidly distribute into the extracellular fluid and equilibrate between the plasma and interstitial compartments.5


Some GBCAs are eliminated unchanged


by glomerular filtration, while others include hepatic clearance (gadoxetate, gadobenate). The terminal elimination T1/2 for GBCAs in people with preserved renal function is 1.3–1.6 hours, and over 96 % of an injected dose is eliminated within 24 hours.6


The hepatic


clearance of gadobenate is 2–4 % and that of gadoxetate is 50 %, and their T1/2 is 1.5–2.0 hours and 1 hour, respectively. In contrast, the T1/2 for the albumin-bound gadofosveset, which is limited to the plasma space and is excreted solely by the kidneys, is 18.5 hours.5


As one would expect, as renal clearance declines, T1/2 becomes prolonged. In patients with stage III chronic kidney disease (CKD), T1/2 increases to approximately 4–8 hours, and in patients with CKD stage IV, T1/2 increases to 18–34 hours, with the total agent excretion time approaching a week or more.5


While agents such as gadoxetate have a


significant hepatic contribution to excretion, impaired kidney function also reduces hepatic drug metabolism. As a consequence, the T1/2 of gadoxetate is also increased two- and threefold in CKD stages III and IV, respectively.5


Animal studies and human observations also support data showing that less stable (linear) agents in settings with long exposure times (impaired renal function) are associated with increased Gd3+ tissue deposition. Rats injected with various GBCAs had a 30-fold increase in Gd3+ skin deposition when exposed to linear-based agents compared with macrocyclic-based agents.7


Gadodiamide


Table 2: Gadolinium-based Contrast Agents and Ligand Characteristics


GBCA Omniscan®


Gadopentetate Magnevist® Gadoversetamide OptiMARK® Gadobenate Gadoteridol Gadoterate Gadobutrol Gadoxetate


Gadofosveset


Brand Name Molecular Charge Structure Linear Linear Linear


MultiHance® Linear ProHance® Dotarem® Gadovist® Primovist® Vasovist®


Published NSF Case Reports


Non-ionic Yes Ionic


Yes


Non-ionic Yes Ionic


Yes


Macrocyclic Non-ionic No Macrocyclic Ionic


No


Macrocyclic Non-ionic Yes Linear Linear


Ionic Ionic


No No


GBCA = gadolinium-based contrast agent; NSF = nephrogenic systemic fibrosis.


are known to promote fibrillogenesis by accelerating collagen formation.20 Evidence suggests that Gd3+ deposition in tissues may lead to fibrosis by inhibiting enzymes involved in the breakdown of collagen (matrix metalloproteinase and tissue inhibitor of metalloproteinases-1) and by stimulating the production of collagen by fibroblasts.21


NSF is a relatively rare disease. By 2010, only 315 cases had been reported in the literature, yet over the previous 20 years, more than 200 million people had been exposed to GBCAs.22


In general, the incidence of NSF in


patients with kidney disease who were exposed to GBCAs has ranged from 0 % to 18 %.23


In addition, non-ionic agents had higher levels of skin deposition than ionic agents, but this characteristic was less important than biochemical characteristics. Even more dramatic findings occurred when linear and macrocyclic agents were injected into 5/6 nephrectomized rats. Skin concentrations were approximately 500 times higher in those exposed to linear-based agents.8


the skin has been described.9


In humans with NSF, gadolinium deposition in In addition, linear-based gadolinium agents


(versus macrocyclic-based agents) are associated with Gd3+ concentrations that are four times higher in the bone samples of normal subjects.10


Nephrogenic Systemic Fibrosis: Rare Disease but Clear Gadolinium Link


NSF is a devastating fibrosing disease that severely affects the quality of life of patients. It was originally described in 15 patients who had previously received, or were in the process of receiving, dialysis,11 and was noted to be a distinct disease entity descriptively named ‘nephrogenic fibrosing dermopathy’.12


Additional subsequent reports


described extracutaneous manifestations, which included involvement of the diaphragm, lung, gastrointestinal tract, and heart.13 led to the current nomenclature ‘nephrogenic systemic fibrosis’.14


Eventually this


The pathogenesis of NSF has clearly been linked to underlying kidney dysfunction. All patients with NSF had either CKD with an estimated GFR of less than 30 ml/min/1.73 m2 (CKD stage IV and V) or AKI.15–17 majority of them had well documented exposure to GBCAs.13


The Multiple


studies have documented Gd3+ deposition in the tissues of patients with NSF.9,18,19


Currently, the exact sequence of events that subsequently leads to tissue fibrosis is a matter of speculation, but Gd3+ and other lanthanides


US NEPHROLOGY


While this rarity has led some to question the link between GBCA exposure and NSF, there are multiple factors that likely explain this disconnect, including lack of NSF recognition, variable risk according to the type of GBCA used, GBCA dose effect, level of kidney function, and patient-specific risk factors.24


Further evidence supporting an association


between GBCA exposure and NSF comes from the dramatic reduction in cases noted following the reduced GBCA exposure of at-risk patients. For example, a recent study examining the incidence of NSF following the implementation of restrictive guidelines found no cases among 52,954 contrast-enhanced MRI examinations in a large academic medical center.25


Macrocyclic agents have recently been implicated as the cause of NSF in a few cases; however, the validity of at least one of these reports has been questioned.27–29


It is critical to appreciate that the associated risk of NSF varies with the different classes of GBCA (see Table 2). The formulation most commonly reported in the literature to have caused NSF is the non-ionic linear agent gadodiamide, followed, less commonly, by the ionic linear agent gadopentetate.26


There is also a relationship


between the dose of GBCA administered and the risk of NSF; the odds ratio for developing NSF in patients receiving multiple doses of gadodiamide was 44.4 compared with 6.67 in those receiving a single dose.30


No cases of NSF occurred in 94 patients given a gadodiamide dose


of 0.1 mmol/kg, whereas 12 cases were seen in 207 patients administered a gadodiamide dose of 0.2 mmol/kg.31


In addition, a higher total


cumulative dose appears to be associated with more severe disease.32 As previously discussed, advanced kidney disease, whether acute or chronic, is a major risk factor for NSF following GBCA exposure. Other proposed factors have been reported to increase the risk of NSF.16


Pro-


inflammatory states such as infection, systemic lupus erythematosis, surgery, vascular injury, acute thromboembolism, and myocardial infarction may facilitate the pro-fibrotic process that occurs when Gd3+ is deposited within tissues. Positively charged protons in metabolic


133


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84