Contrast-induced nephrotoxicity: clinical landscape.

Over 80 million doses of iodinated intravascular contrast media (CM) were administered in the most recent tabulations of 2003, corresponding to approximately 8 million liters, making it one of the highest volume medical drugs used compared to any other pharmaceutical. The evolution of CM has focused on minimizing adverse events by eliminating ionicity, increasing hydrophilicity, lowering osmolality and increasing the number of iodine atoms per molecule. Contrast media are classified into three general categories based on their osmolality relative to blood: high osmolar (5 times or greater than blood), low osmolar (2-3 times blood) and iso-osmolar (the same as blood). All imaging modalities that employ CM, especially computerized tomography (CT), have shown rapid growth. In the last two decades, the use of CT scanning has increased by 800%. From 1979 to 2002, the number of cardiac catheterization procedures in the USA increased by 390% and in Europe from 1992 to 1999 by 112%. There is a general consensus that renal insufficiency and diabetes are major risk factors for contrast-induced nephropathy (CIN), particularly when co-existing. The US Renal Data System documents a 'relentless' increase in kidney failure, projecting a 90% increase by 2010. Diabetes affects 194 million people worldwide and the number is anticipated to increase by 75% by 2025. The unavoidable conclusion is that patient exposure and prevalence of risk factors for CIN will continue to increase.

Renal effects of contrast media.

A brief overview of the renal effects of contrast media (CM) is presented. Many of the physiologic actions of CM are indistinguishable from those of mannitol matched for osmolality. The pathophysiology of CM-induced acute renal failure remains obscure.

Preliminary evaluation of Hexabrix for temporomandibular joint arthrography.

A double-blind randomized study of ten patients compared Hexabrix 32% to Renografin-60 in TMJ arthrography. Equivalent volumes of contrast material were injected under fluoroscopic observation, with film quality and patient subjective response graded independently by three radiologists. In immediate arthrogram quality, Hexabrix was rated excellent; Renografin-60 was rated good. For 10-minute radiographs, Hexabrix had a good to excellent rating; Renografin-60 rated fair to good in image quality. Significantly less pain was experienced with Hexabrix.

The effects of media viscosity on hemodynamics in selective arteriography.

Radiographic contrast media used for arteriography are generally more viscous than plasma or blood; however, little consideration is given to the hemodynamic effects of contrast media viscosity. In this study, in vivo and in vitro injection of isotonic solutions of saline and polyvinylpyrrolidone, having viscosities from 0.8 to 26 centipoise, have been made. The results demonstrate that, when the viscous saline reaches the microcirculation, the resistance to flow increases. The viscous saline thus significantly decreases flow immediately after the injection. At that time the pressure in the artery equals aortic pressure, but the local vascular resistance is elevated because of the viscous material present in the arterioles. Viscous contrast media would cause similar hemodynamic changes during and immediately following an injection. The effects of contrast media hypertonicity, however, modify the viscosity-related changes shortly after the contrast media reaches the capillaries.

Cardiovascular responses to the intravertebral artery injection of hypertonic contrast media in the dog.

Central nervous system-mediated cardiovascular responses to contrast medium (CM) are believed the result of a vagal or of a sympatholytic response; these effects may be enhanced in the setting of dehydration. The purpose of this investigation was to evaluate neurally mediated effects of intravertebral artery CM injections on blood pressure (BP), heart rate (HR) and regional vascular resistances in euvolemic and dehydrated dogs. Animal preparation consisted of food and water ad libitum (n = 7) vs. 2.0 ml/kg i.m. furosemide and 48 hours thirsting (n = 7). During pentobarbital anesthesia BP, HR and renal and femoral blood flows were continuously monitored and meglumine iothalamate 60% (1 ml/kg) injected via a left vertebral artery catheter at 3 ml/sec; matched volume injections of normal saline served as control. Decreases in BP, HR and femoral and renal vascular resistances post CM injection were observed in the first 10 seconds before the CM had reached the systemic circulation. Significant decreases in both BP (-10.6 +/- 1.7%) and HR (-11.5 +/- 1.6%) post CM injection were noted with dehydration (n = 7). In the euvolemic dogs (n = 7) the decrease in HR (-7.3 +/- 2.0%) was significant but the decrease in BP (-3.9 +/- 2.4%) was not. The decrease in femoral vascular resistance was -22.7 +/- 9.0% in euvolemic dogs and -21.9 +/- 8.8% in dehydrated dogs. No significant changes were noted with the intravertebral artery injections of normal saline in control euvolemic and dehydrated animals. The early cardiovascular responses to CM suggest a direct action on the vasomotor center of the medulla. The effects on BP and HR are more severe in the dehydrated than in the euvolemic state.

Tissue fluid shifts during renal arteriography with conventional and low osmolality agents.

The osmotic effects caused by conventional and low osmolality radiopaque agents have been studied in the isolated perfused canine kidney. Changes in vein flow, hematocrit, osmolality, and iodine content were measured at injection doses of 0.25 and 0.5 ml/kg (300 mgI/ml). Increases in osmolality and decreases in hematocrit were significantly greater with the conventional ionic monomer meglumine/sodium diatrizoate than with the low osmolality agents iohexol, iopamidol, and ioxaglate. The standard renal vein flow response for all agents was an increase (loss of renal water) followed by a decrease (gain of renal water). Diatrizoate produced the greatest increase in outflow at 0.25 ml/kg, but the differences between agents were not statistically significant. At the 0.5 ml/kg dose the differences in peak renal vein flow between agents were negligible. Renal vein iodine was highest with the dimer, ioxaglate and lowest with the diatrizoate. The nonionics iohexol and iopamidol produced essentially the same renal vein iodine levels and clearance. The new low osmolality agents have significantly less effect on osmolality and hematocrit and produce higher venous iodine levels than a conventional ionic monomer. The only difference between the low osmolality agents was the higher venous iodine seen with the dimer ioxaglate.

A comparison of the hemodynamic responses to metrizamide and meglumine/sodium diatrizoate in canine renal angiography.

Selective renal angiography causes a biphasic change in renal blood flow and vascular resistance. In this study, 5 ml of meglumine/sodium diatrizoate (288 mg I/ml, 1455 mosm/kg), metrizamide (290 mg I/ml, 593 mosm/kg), isontonic saline (287 mosm/kg) and hypertonic saline (1500 mosm/kg) were injected into the renal arteries of seven adult mongrel dogs to determine whether the minimum flow (or maximum resistance) was related to the osmolality of the injected agent. The maximum resistance response was significantly smaller for metrizamide (20 +/- 4%) and isotonic saline (19 +/- 2%) than for diatrizoate (36 +/- 6%) or hypertonic saline (50 +/- 7%). Hypertonic saline produced two distinct types of responses: the typical biphasic response or a severe immediate drop in flow. Thus the maximum resistance response was related to agent osmolality. The "injection artifact," or flow changes occurring during the injection, were different for the four agents, and these differences appeared correlated to agent viscosity. Although both contrast media caused relatively small changes in renal hemodynamics, metrizamide caused significantly smaller changes than meglumine/sodium diatrizoate.

Evaluation of various contrast agents for improved arthrography.

In the canine knee joint the monomer methylglucamine iothalamate, the dimer methylglucamine iocarmate, and the nonionic contrast agent metrizamide were examined for use in arthrography. A total of 104 injections were performed with equal iodine concentrations (280-282 mg/ml) and volumes (4 ml) of the three contrast agents. These were evaluated using radiographic comparison and iodine estimations of the joint fluid at various times after injection. Radiographically the dimer was superior, followed by metrizamide and then the monomer. The greatest amount of total iodine within the joint fluid at various times after injection was found with the dimer. Iodine concentrations in the joint fluid were similar for the dimer and metrizamide, both greater than with the monomer.

Epinephrine enhanced knee arthrography.

The effect of .3 cc of 1:1000 epinephrine on iodine concentration, total iodine content, fluid volume and radiographic quality was evaluated in knee arthrograms in dogs. With the addition of epinephrine the iodine concentration and total iodine content were significantly higher initially and remained significantly higher than in controls over a one hour period. The fluid volume in the knee was significantly lower with epinephrine. Initially both contrast absorption and dilution have major effects in decreasing iodine concentration. With increasing time the effect of contrast absorption becomes the major factor, having a two of three times greater effect on decreasing iodine concentration. With epinephrine radiographs were judged significantly better early and while the quality deteriorated rapidly in the controls the enhanced quality with epinephrine persisted up to one hour. Epinephrine is a very useful adjunct in enhancing the quality of knee arthrography.

Renal renin and hemodynamic responses to selective renal artery catheterization and angiography.

Selective renal artery catheterization and renal angiography are commonly performed diagnostic procedures; however, the effects of these procedures on renal blood flow (RBF) and renin release have only been partially described. A biphasic RBF response has been well documented furing selective angiography in dogs. The renal autoregulatory mechanisms governing the responses are uncertain. The renin-angiotensin system and the major parameters of contrast media, hypertonicity and viscosity, have been suggested as important factors. In the canine model, we examined the acute changes in renal venous renin activity along with the renal hemodynamic effects of hypertonicity and viscosity. Our results do not support a primary effect mediated by the renin-angiotensin system. Hypertonicity and the contrast medium per se are significant in active and passive autoregulatory responses at the smooth muscle cellular level.

Effects of contrast media on renal function and subcellular morphology in the dog.

The effects of intravenous contrast media (CM) on renal excretory function and subcellular morphology are examined in this animal investigation. A decrease in GFR (12.0 +/- 1.6 vs. control 30.2 +/- 2.5 ml/min) was observed when renal function was evaluated by means of the artero-venous extraction method with Tc99m DTPA and the anticipated inverse relationship to urinary flow (Vml/min) noted. An artifactual increase in GFR (43.5 +/- 10.0 vs. control 39.1 +/- 3.8 ml/min) was observed using the timed urinary clearance of inulin. V(ml/min) increased four-fold (0.6 +/- 0.16 control vs. 2.7 +/- 0.7 ml/min; P less than .05) over the first five minutes after injection of CM. Urine osmolality initially approached isotonicity and then returned toward preinjection values. Osmolal clearance (Cosm) rose 2.5 times (1.4 +/- 0.3 control vs. 3.7 +/- 1.0 ml/min; P less than .05). The fractional excretion of both Na+ (FENa+) and K+ (FEK+) increased. A comparison of urinary osmolality vs. time after injection of CM confirms a nonspecific osmotic effect on tubular (and hence total urine) flow. The hemodynamic effects of CM on the kidney via the i.v. route reflect a predominant and nonspecific osmotically mediated vasodilation. No significant light or electron microscopic changes were observed. These findings suggest that the major renal physiologic actions of hypertonic CM are a nonspecific response to agent osmolality.

Effects of the magnetic resonance contrast medium ferrioxamine methanesulfonate on systemic and renal hemodynamics in the anesthetized dog.

Ferrioxamine methanesulfonate (S-FDF) is a new magnetic resonance (MR) contrast agent developed to improve magnetic resonance imaging of the abdomen and pelvis. This stable complex of deferoxamine methanesulfonate and iron is excreted in the urine by glomerular filtration modified by active renal tubular resorption. This study examines the acute systemic and renal hemodynamic responses to this agent after intravenous administration either as an infusion of 25 mg/kg over 5 minutes or as a rapid bolus at a dose of 50 mg/kg. In eight anesthetized dogs, renal plasma flow (RPF) was measured with an electromagnetic flowmeter, and GFR was determined by the renal extraction of technetium-99m-DTPA. Mean arterial pressure (MAP), pulse rate, and a lead II ECG were assessed. At a dose of 25 mg/kg over 5 minutes, MAP decreased significantly (control 146.0 +/- 6.5 mm Hg vs. 107 +/- 18 mm Hg at 2 minutes; P less than .05). In two of the eight animals, the MAP dropped below 60 mm Hg. Significant decreases in GFR and RPF also were noted. All four of the animals receiving the rapid injection of S-FDF experienced profound hypotension (MAP less than 50 mm Hg). The drop in heart rate from 152 +/- 11.6 bpm to 121 +/- 4.9 bpm was associated with a marked depression of the ST wave in the lead II ECG. Further animal studies are needed to assess the mechanism of toxicity and a potential synergism of action with pentobarbital anesthesia.

Mechanism of the renal response to contrast medium in dogs. Decrease in renal function due to hypertonicity.

Radiographic contrast media (CM) (meglumine/sodium diatrizoate-76%; 1650 mOsm/kg) and other hypertonic solutions induce renal vasoconstriction by an unknown mechanism. In anesthetized dogs, renal blood flow (RBF) was measured with an electromagnetic flowmeter and filtration fraction (FF) and glomerular filtration rate (GFR) by the renal extraction of technetium-99m tin chelate. Ureteral pressure (UP) and wedged renal venous pressure (VP) were measured as indices of intrarenal pressure. Measurements of renal length (L), along with pressures, made it possible to examine the compliance of the system. A 4-cc intrarenal bolus of CM caused a 59% reduction in GFR (control: 0.63 +/- 0.04 to 0.26 +/- 0.04 ml/min X g, mean +/- SEM), in association with a 23% reduction in RBF (control: 3.10 +/- 0.11 to 2.39 +/- 0.26 ml/min X g) and a 44% decrease in FF (control: 0.32 +/- 0.01 to 0.18 +/- 0.03). These responses were compared with a 3-microgram intrarenal bolus of norepinephrine (NOREPI) which resulted in a 79.0 +/- 7.5% reduction in RBF, 68.3 +/- 7.3% reduction in GFR and 42.6 +/- 15.6% increase in FF. The NOREPI-induced vasoconstriction caused transient decreases in renal L, UP, and VP, whereas the CM-induced decrease in renal blood flow was associated with increases in these parameters. In studies employing ureteral occlusion to elevate intrarenal pressure, the magnitude (area, cm2) of the CM-induced decrease in renal perfusion was accentuated with increased UP (r = 0.79, n = 24, P less than 0.001). The CM-induced increase in renal L, UP, and VP must reflect osmotic forces and an increase in intrarenal pressure. The decreases in FF and GFR probably reflect Starling forces in the glomerular capillaries, with osmotic transients dominating. The results suggest a mechanical mechanism for the CM-induced decrease in RBF.

Acute systemic and renal hemodynamic effects of meglumine/sodium diatrizoate 76% and iopamidol in euvolemic and dehydrated dogs.

We examined the acute systemic and renal hemodynamic effects of intravenous meglumine/sodium diatrizoate-76% and iopamidol in euvolemic and dehydrated dogs. The physiologic responses were compared with acute changes in the level of an endogenous heparin-like material (EHM). One of eight dehydrated dogs receiving diatrizoate (2 ml/kg) had an immediate vomiting reflex associated with a very significant decline in all measured renal hemodynamic parameters; none of eight dehydrated dogs receiving iopamidol experienced a similar reaction. EHM levels did not correspond to the magnitude of the physiologic responses following either iopamidol or diatrizoate. Significant differences between iopamidol and diatrizoate were noted when comparing the magnitude of the decrease in systemic pressure (- delta 3.8 +/- 3.02, iopamidol, n = 8; vs. - delta 19.4 +/- 7.3 mm Hg, diatrizoate, n = 8; P less than .03), increased renal plasma flow (+ delta 6.2 +/- 4.9, iopamidol, n = 8; vs. + delta 33.7 +/- 8.0 ml/min, diatrizoate, n = 8; P less than .05), and decreased filtration fraction (- delta 0.09 +/- 0.01, iopamidol, n = 8; vs. - delta 0.14 +/- 0.02, diatrizoate, n = 8; P less than .03). There was no significant difference in the decrease in glomerular filtration rate (- delta 7.4 +/- 1.0, iopamidol, n = 8; vs. - delta 9.3 +/- 1.3, diatrizoate, n = 8; P greater than .05), since the marked drop in filtration fraction occurring with diatrizoate was counterbalanced by the marked increase in renal plasma flow. Acute systemic and renal hemodynamic effects are significantly lessened when comparing iopamidol with diatrizoate.

A comparison of clearance and arteriovenous extraction techniques for measurements of renal hemodynamic functions.

No previous studies have directly compared timed urine collections (UV/P) vs. arteriovenous (A-V) extraction methods for determination of renal function in whole kidney preparations. We examined different markers and techniques for assessing renal plasma flow (RPF), filtration fraction (FF), and glomerular filtration rate (GFR) in both steady-state and rapidly changing conditions following 2 ml/kg bolus intravenous injections of either Renografin 76% (meglumine/sodium diatrizoate-76%) or hypertonic mannitol 25%. During steady-state conditions, excellent correlations were obtained when comparing markers and techniques. Thus, timed urinary clearances of inulin vs. 99m-technetium DTPA (Tc) had a correlation coefficient (R) of .96 (P less than .01; n = 16), and the A-V extraction technique of inulin vs. Tc as determinants of GFR showed a correlation of R = .98 (P less than .01; n = 15). The timed urinary clearance of inulin vs. the A-V extraction of inulin for glomerular filtration gave a correlation of R = .93 (P less than .01; n = 15). The clearance of para-aminohippurate (PAH) divided by the extraction of PAH vs. flow determinations using the electromagnetic flowmeter gave a correlation of R = .92 (P less than .01; n = 16). The anticipated decrease in GFR following contrast medium and hypertonic mannitol was observed using the A-V extraction technique, whereas an artifactual, exaggerated increase in GFR was observed using the timed urine collection technique. Similarly, we noted an exaggerated increase in RPF using CPAH/EPAH as the methodology. We conclude that rapid changes in renal hemodynamics may be measured accurately using the A-V extraction technique but not with clearance techniques requiring timed urine collections.

Renal handling and physiologic effects of the paramagnetic contrast medium Gd-DOTA.

Gadolinium DOTA (Gd-DOTA) is a magnetic resonance (MR) contrast agent similar to Gd-DTPA but with greater stability in vitro. The effects of a high intravenous dose (0.5 mmol/kg) of Gd-DOTA (1360 mOsm/kg) on renal excretory function and its general systemic effects are examined in this animal study. This dose was selected to accentuate and better define the qualitative nature of these effects. A decrease in arterial pressure of 8% (131.9 +/- 6.8 at 120 minutes versus a control of 142.8 +/- 3.7 mm Hg, mean +/- standard error of mean, no significant change in electrocardiogram (ECG) lead II, a 16% increase in renal blood flow (106.0 +/- 5.4 at 7.5 minutes versus 91.2 +/- 3.2 ml/min), and a decrease in arterial hematocrit of 9% (38.9 +/- 1.5 at 120 minutes versus 41.9% +/- 1.7%) were noted. In general, qualitatively similar effects have been noted as a nonspecific effect of other hyperosmolar solutions. The filtration fraction decreased (0.23 +/- 0.01 at 7.5 minutes versus 0.28 +/- 0.02) followed by a rapid return to baseline values. No significant change was noted in glomerular filtration rate throughout the experimental protocol. Urine flow increased nearly 1.5-fold and osmolal clearance (Cosm) increased approximately 1.5 times. A natriuresis occurred as the fractional excretion of sodium (FENa+) increased from a control value of 3.5 +/- 0.3 to 5.2 +/- 0.5 at 7.5 minutes. The systemic and renal physiologic effects of high-dose intravenous Gd-DOTA on the kidney reflects a nonspecific, osmotically induced alteration. These data suggest that the main systemic and renal physiologic actions of Gd-DOTA are a nonspecific response to agent osmolality that is similar qualitatively to conventional, water-soluble contrast media.

Ioxilan, a third generation low osmolality nonionic contrast medium. Systemic and renal hemodynamic effects.

The choice between high cost, low toxicity nonionic contrast media (CM) and low cost ionic CM poses a dilemma for radiologists. Ioxilan, a third generation nonionic CM, is obtained by simple conversion from an ionic CM. To examine how this economically promising, low osmolality CM (570 mOsm at 300 mgI/ml) affects canine systemic and renal hemodynamics, IV bolus injections of 350 mgI/ml at 2 ml/kg of Iohexol and Ioxilan were compared. Satisfactory nephrograms and pyelograms were produced by both agents, without significant differences. The effects on systemic and renal hemodynamics were minimal and statistically equal for both CM. The acute systemic and renal responses and radiographic image quality of Ioxilan and Iohexol confirm that the two compounds are biologically equivalent, and that the novel molecular design employed in Ioxilan to achieve very low osmolality also provides good biological tolerance.

Gadolinium-DTPA transplacental transfer and distribution in fetal tissue in rabbits.

RATIONALE AND OBJECTIVES: The authors assessed to what extent the commonly used the magnetic resonance imaging contrast agent, gadopentetate dimeglumine, crosses the placenta. METHODS: Eight pregnant rabbits in the third trimester were injected with 0.1 mmol/kg of gadopentetate dimeglumine, and killed 5, 15, 30, or 60 minutes after injection. Placental and fetal tissues were analyzed for gadolinium content. RESULTS: Placental concentrations of gadolinium were initially high (16.6 +/- 3.4 micrograms/gram) and then declined with a biexponential pattern. Initial gadolinium levels in the fetal organs were low and remained so except for the fetal kidneys, which showed increased levels of gadolinium from 4.3 +/- 1.1 micrograms/gram at 5 minutes to 6.8 +/- 1.8 micrograms/gram at 60 minutes. CONCLUSIONS: The results indicate that gadolinium does cross the rabbit placenta, and that concentrations in the placenta and the fetal urinary tract are sufficient for imaging as well as possible fetal toxicity.

A reappraisal of the radiologic findings of acute inflammation of the epiglottis and supraglottic structures in adults.

PURPOSE: To evaluate the radiologic characteristic of acute inflammation of the epiglottis and supraglottic structures in adults. METHODS: The clinical and radiographic findings in 27 adult patients with epiglottitis (average age, 43 years; range, 28 to 81 years) were compared with those of a control group of asymptomatic subjects (n = 15; average age, 48 years; range, 24 to 79 years). Unusual clinical aspects in the current series included two patients who were positive for human immunodeficiency virus, 1 with acquired immunodeficiency syndrome and Kaposi sarcoma, 3 with emphysematous epiglottitis, 1 with abscess formation, and 1 with laryngeal carcinoma. One patient required emergency tracheostomy. One patient died of pneumonia. RESULTS: The ratio of the soft-tissue parameters to the anteroposterior width of the C-4 vertebral body yielded three key parameters of high statistical significance in adult epiglottitis. The ratio of the width of the epiglottis to the anteroposterior width of C-4 should not be greater than 0.33 (sensitivity, 96%; specificity, 100%). The ratio of the prevertebral soft tissue to C-4 should not exceed 0.5 (sensitivity, 37%; specificity, 100%) and the ratio of the width of the hypopharyngeal airway to the width of C-4 should be less than 1.5 (sensitivity, 44%; specificity, 87%). The aryepiglottic folds were enlarged in 85%, and the arytenoids were swollen in 70% of the patient population (specificity, 100%). CONCLUSION: These defined radiologic parameters should aid in the diagnosis of acute epiglottitis in adults.

Radiographic assessment of asymmetry of the mandible.

PURPOSE: To assess the relationship between mandibular asymmetry and disorders of the temporomandibular joint. METHODS: We used advanced imaging of the temporomandibular joint to distinguish different causes of mandibular asymmetry. MR imaging and arthrography were applied to the temporomandibular joints of 11 patients presenting with mandibular asymmetry. RESULTS: Condyle hyperplasia was identified as the cause of the asymmetry in 5 patients. In the other 6 patients the mandibular condyle was normal on the long side, but the short side of the face demonstrated a small condyle head, short condyle neck associated with disk displacement, internal derangement, and degenerative joint disease of the temporomandibular joint. CONCLUSIONS: These observations suggest that both condyle hyperplasia on the long side of the mandible and disk displacement and degenerative joint disease of the temporomandibular joint on the short side can cause mandibular asymmetry. It was concluded that MR imaging or arthrography can be valuable for understanding the cause of mandibular asymmetry and be effective in treatment planning.