|Year : 2008 | Volume
| Issue : 2 | Page : 174-182
|Contrast Media Nephropathy: In Depth Review
N Hussain1, T Al Otaibi2, M.R.N Nampoory2
1 Department of Medicine, Mubarak Al-Kabeer Hospital, Kuwait
2 Hamad Al Essa Organ Transplant Centre, Kuwait
Click here for correspondence address and email
|How to cite this article:|
Hussain N, Al Otaibi T, Nampoory M. Contrast Media Nephropathy: In Depth Review. Saudi J Kidney Dis Transpl 2008;19:174-82
| Introduction|| |
Contrast nephropathy (CN) remains a common cause of acute renal failure in patients undergoing radiocontrast study.  It is the third leading cause of hospital-acquired acute renal failure (ARF) after hypotension and surgery.  CN is associated with both short- and long-term morbidity and mortality,  with estimates of in-hospital mortality rates are as high as 34% in patients who develop ARF compared with 7% in those who do not.  There is continued controversy about the pathogenesis of this entity despite the better understanding of its risk factors.
The purpose of this article is to review recent developments in the area of CN and means of minimizing the risk or preventing this important problem.
| Clinical Features of CN|| |
Many different definitions of CN appear in the literature. In many studies, CN is defined as an increase in serum creatinine level by more than 25% of the baseline value or by more than 0.5 mg/dL, which appears within the first 48 hours after radiocontrast administration.  Depending on the definition of CN and the presence of co-morbidities, the incidence of this complication varies markedly.
Clinically, CN is diagnosed when an abrupt deterioration of renal function upon radiocontrast exposure in the absence of other causes of renal failure such as atheromatous embolic disease, ischemia, and other nephrotoxins. Typically, CN presents as an asymptomatic, non-oliguric rise in serum creatinine 24 to 48 hours after contrast exposure, peaks within three to five days and typically resolves with a return to baseline serum creatinine by seven to ten days.  The time course for severe cases is prolonged with an increase of serum creatinine up to ten days and a gradual return over the following two to four weeks. Examination of the serum and urine are relatively nonspecific. Urinalysis usually yields renal tubular epithelial cells, granular casts and lowgrade proteinuria; however the urinalysis may also be bland. Occasionally, calcium oxalate or uric acid may be observed. The fractional excretion of sodium is typically less than 1%, mimicking extracellular volume depletion. ,
| Pathogenesis of CN|| |
The pathogenesis of CN is poorly understood. It is believed that four dominant injury pathways exist, and it is likely that these factors function together in concert to induce CN in a given patient.  First, intrarenal vasoconstriction causes renal medullary hypoxia that culminates in cell detachment, apoptosis and necrosis.  Since the renal medulla is normally deficient in oxygen, with a PaO 2 of 10 to 20 mmHg, it is readily susceptible to further hypoxia.  Second, radiocontrast medium may precipitate in the distal tubule lumen, along with glycoproteins, forming casts.  Third, radiocontrast medium may directly damage tubular cells via the difference in osmolality or direct cytotoxicity.  Finally, reperfusion injury may occur after initial tissue ischemia via reactive oxygen species production.  Alteration of renal hemodynamics, namely vasoconstriction, is the primary proposed mechanism of CN and is affected by a variety of factors. These include adenosine, calcium and endothelin. , There also appears to be an association between comorbid conditions such as age and diabetes that decrease vasodilating factors including nitric oxide and prostaglandins. 
| Risk factors for CN|| |
Mild and transient decrease in glomerular filtration rate occurs after contrast administration in almost all patients.  Whether a patient develops a clinically significant ARF, however, depends very much on the presence or absence of certain risk factors. Common risk factors include preexisting renal insufficiency, diabetes mellitus with concurrent renal insufficiency, intravascular volume depletion, type and dose of contrast media used, and older age. 
Normal renal function
It is currently believed that individuals with normal renal function are not at risk to develop CN. Retrospective studies estimate incidence of CN around 0.1% . 
Diabetes is frequently considered an independent risk factor for CN. However, a study by Parfrey et al found that diabetic patients with normal renal function are not at increased risk. The incidence of CN in diabetic patients with normal renal function was 3.4%, not significantly different from the 1.5% in the nondiabetic control group. They concluded that the risk of CN was minimal in patients with diabetes with normal renal function.  Multiple other studies quoted in this paper found increased incidence of CN in patients with moderate to severe renal insufficiency. 
Preexisting renal insufficiency
As one's serum creatinine increases, the incidence of CN increases. Barrett et al reported 6% incidence of CN with a concurrent baseline serum creatinine 1.4 mg/dL.  This incidence has also been reported by others.  The probability of requiring dialysis after the development of CN in this group ranges from 0.04% to 48% as the precontrast creatinine clearance decreases from 50 to 10 mL / min. 
Diabetes mellitus with concurrent renal insufficiency
This group of patients carries the greatest risk of development of CN and severe renal dysfunction often requiring acute or chronic hemodialysis.  of the requirement of dialysis increases from 0.2% to 84% as the precontrast creatinine clearance decreases from 50 to 10 ml/min.  Wexler et al also found 3.7 times higher risk of CN in diabetic patients with renal insufficiency than those with renal insufficiency alone.  Therefore, patients with preexisting renal insufficiency and diabetes with presumed micro and macrovascular disease are at much higher risk of developing CN.
First generation ionic monomers are extremely hyperosmotic at 1500-1800 mosmol/kg and associated with higher rates of nephrotoxicity. It was initially believed that the use of a second generation nonionic low osmolar contrast would be associated with a decline in CN in all patient populations. The second generation agents such as Optiray have measured osmolality of 600-850 mosmol/kg, but they remain quite hyperosmolar when compared to plasma (300 mosm). In studies of patients with moderate renal insufficiency, serum creatinine between 1.4 and 2.4 mg/dL, the nonionic low osmolar agents were associated with a low incidence of CN.  Wexler et al found the incidence of CN in ionic contrast media to be more than double that secondary to the nonionic low osmolar contrast media, primarily in patients with renal insufficiency with and without diabetes mellitus.  A more recent randomized controlled trial by Rudnick et al  confirmed the findings of Wexler et al  by comparing the incidence of CN between high-and low osmolar contrasts. With the use of low-osmolar contrast, these investigators found a significant 15% decrease of risk of CN in diabetic patients with serum creatinine > 1.5 mg/dL; a 3% decrease of risk of CN was observed in the nondiabetic renal insufficiency patients, and no difference was observed in the non azotemic patients.  Low-osmolar contrast media have become standard practice in most institutions and should always be used in the high-risk patients.
Newer generation nonionic contrast agents are available with iso-osmolar concentration at 290 mosmol/kg and may decrease risk of CN. ,, However, a recent study demonstrated a decrease in medullary oxygen level in both lowand iso-osmolar agents, which indicate that both low-and iso-osmolar agents are able to potentiate ischemic injury and CN. 
Several other factors influence the development of CN. Advanced age is associated with a dominance of renal vasoconstrictive instead of vasodilatory forces. This may be related to decrease prostaglandin E2, a renal vasodilator, in healthy older people rendering the kidney vulnerable to contrast induced ischemia. 
Intravascular volume depletion, NYHA class III and IV congestive heart failure and hepatic cirrhosis are also associated with increased risk of CN.  It is currently debated whether multiple myeloma is an independent risk factor for development of CN.  However, multiple myeloma is frequently associated with intravascular volume depletion and renal insufficiency with increased risk of CN.
| Strategies for the prevention of CN|| |
Contrast administration, more often than not, is a planned procedure, and high risk patients can often be identified before the investigation. Therefore, avoidance or minimization of the risk of CN is possible.
The decision to give contrast should reflect a risk-to-benefit ratio established for an individual patient. When contrast administration is deemed appropriate, the lowest dose of contrast possible should be used, and any risk factors for CN should be corrected or controlled before the administration of the contrast media.
A variety of specific measures have been used to prevent CN, particularly in high risk patients:
Hydration with 0.45% (half - isotonic) or 0.9% (isotonic) saline is more effective than placebo in minimizing the incidence of CN. A prospective, randomized, controlled, open-label study by Mueller et al  randomly assigned 1620 patients scheduled for elective or emergency coronary angioplasty to receive isotonic (n = 809) or half-isotonic (n = 811) hydration started the morning of the procedure for elective interventions and immediately before emergency interventions. The incidence of CN was 0.7% with isotonic and 2.0% with half-isotonic hydration (P = 0.04).  Three predefined subgroups benefited in particular from isotonic hydration: women, diabetics, and patients receiving 250 mL or more of contrast.  The authors found isotonic hydration to be superior to half isotonic hydration in the prevention of CN. However, this data should be taken with a grain of salt, as glucose was included in the 0.45% NS algorithm. This is important, as many of the aforementioned studies did not have glucose included in their study protocols. Furthermore, as demonstrated in stroke studies, glucose exposure was often detrimental and expanded the probability of ischemia in the renal medulla. A study comparing normal saline to 0.45% NS without glucose may resolve the question.
Merten et al  illustrated a significant decline in CN in patients receiving a sodium bicarbonate infusion in a prospective, single-center trial. They randomized 119 patients with stable serum creatinine levels of at least 1.1 mg/dL to receive either normal saline or sodium bicarbonate as a bolus 3 mL/kg/h for one hour before and 1 mL/kg/h for six hours after contrast infusion. CN was defined as an increase of 25% or more in serum creatinine within 48 hours. CN occurred in 8 patients receiving NS and only 1 patient receiving sodium bicarbonate infusion. This difference was significant and resulted in a follow-up registry of 191 patients who received sodium bicarbonate prophylactically and developed CN in only 1.6%, confirming the results of the clinical trial.
N-acetylcysteine (NAC) may prevent CN by two mechanisms. First, It may combine with nitric oxide, resulting in more stable storage of nitric oxide (NO),  better vasodilatory properties of NO on the kidney, better tolerance to the vasodilatory effects of nitrates, improvement of renal hemodynamics, and decreased medullary hypoxia.  second, it has the ability to scavenge oxygen-free radical, possibly preventing direct oxidative tissue damage that occurs in patients receiving contrast.  Recently, Tepel et al  demonstrated that the antioxidant NAC decreased the incidence of CN in patients with chronic kidney disease undergoing contrast infusion for computed tomography with a relative risk of 0.11, establishing NAC as a potent prophylactic agent against CN.
McNeill et al  performed a double-blind, placebo-controlled study on 43 patients with baseline serum creatinine > 1.5 mg/dL under going cardiac catheterization. All patients were prehydrated with 1ml/kg/h of 0.45% NS, 21 received five doses of 600 mg of NAC with two doses administered before the procedure, and 22 received placebo. An increase of serum creatinine of 25% or greater from baseline defined CN. The authors found a significant reduction in CN in patients receiving NAC (1 patient developed CN in the experimental arm compared to 7 in the placebo group, p < 0.05). Those who received placebo had continued increase in serum creatinine measurements after 24 hour.
A recent meta-analysis by Alonso et al  reviewed the results of eight double-blind and unblind randomized controlled trials using NAC for the prevention of CN in humans older than 18 with renal insufficiency (baseline creatinine ranging from 1.3 to 2.8 mg/dL). Intravenous fluid administration was considered standard therapy in all studies, but varying algorithms were used between the studies. Two studies used 0.9% saline, while the other six used 0.45% saline with varying pre and post procedure timing. However, all patients received 1 ml/kg/h, and most received hydration 12 hours before and after contrast administration. The mean radio contrast volume ranged from 75 to 230 mL. Seven studies used low-osmolar, and 1 used iso-osmolar contrast media. NAC was administered orally in 7 studies. Five studies used 600 mg po bid for four doses, one used 400 mg po bid for four doses and another used 1,200 mg prior to contrast exposure. The last study administered IV N-acetylcysteine at 150 mg/kg 30 minutes prior to exposure followed by 50 mg/kg over four hours after exposure to contrast media. There were 885 patients included in these studies. Overall, there were 35 cases of CN in the NAC group compare to 82 in the control group receiving hydration alone. Overall relative risk associated with NAC use was 0.41 (p < 0.01).
3. Calcium channel antagonists
Theoretically, calcium channel blockers would antagonize afferent arteriole constriction thereby maintaining glomerular filtration rate (GFR). As a class, calcium channel blockers have been shown to retard the decline in GFR and the duration of intrarenal vasoconstriction after contrast exposure. Russo et al examined the protective role of nifedipine in a randomized, double-blind, placebo-controlled study. They found that nifedipine was able to prevent the anticipated deterioration in renal hemodynamics induced by high-osmolar contrast. Patients who received placebo had a significant decrease in renal blood flow as measured by enzymuria (inulin and para-aminohippurate). However, this study only took measurements up to two hours after contrast administration, only included low-risk patients (none had renal insufficiency or diabetes), and did not mention the fluid hydration rates.  Serum creatinine measurements were not followed up to 72 hours after contrast; the study failed to analyze the "gold standard," if you will, of measured serum creatinine as most studies mentioned in this paper. Two other studies that showed "benefit" from calcium channel blockade used similar protocols to the Russo's study, measuring only urine enzymes, not serum creatinine. It should be noted, though, that the above studies demonstrated a significant preservation of GFR and amelioration of enzymuria, suggestive of protective effect of the calcium channel blockers against CN.
A more recent study by Spangberg-Viklund et al  randomized 27 patients with normal to moderate renal insufficiency (15 diabetics and 12 non-diabetics) to receive either oral felodipine XR or placebo in addition to at 2 L / 24 h of intravenous hydration. Patients in the experimental arm revealed a significant increase in serum creatinine from baseline, while the patients receiving placebo did not. Furthermore, the authors suggested that felodipine may have mild renoprotective benefit in those with more advanced renal insufficiency after subgroup analysis.
Unfortunately, firm conclusions cannot be drawn from the published trials, as study populations are small. Moreover, the measured outcomes, protocols for hydration, and medication administration dosage and duration are not standardized. Large, randomized, prospective trials are required to further delineate the role of calcium channel blockade in CN.
Theoretically, mannitol is believed to increase tubular flow rates and reduce the time of contrast exposure in addition to increasing atrial natriuretic peptide production thereby increasing GFR. Early studies suggested benefit with a relative risk reduction of 71% in patients receiving mannitol immediately after contrast infusion.  The control group which received no therapy, including hydration, limited the validity of this study. A follow-up study to the Anto  trial addressed this deficit and found no significant difference between the mannitol and the saline hydration groups. However, a study analyzing the benefit of mannitol helped develop a significant change in the strategy to prevent CN. This randomized, prospective trial by Solomon et al  found patients (baseline serum creatinine of > 1.6 mg/dL) who received 1 mL/ kg/h IV 0.45% saline had a significantly reduced incidence of CN (11%) compared to those who received a combination of saline and mannitol (28%) or saline and furosemide (40%), establishing the renoprotective benefit of hydration. Given these results, it would be wise to avoid mannitol prior to or after contrast media infusion.
Theophylline acts as an adenosine antagonist and thereby decreasing intrarenal vasoconstriction. A number of studies have used varying doses of theophylline with conflicting results. Four randomized, prospective studies found significant less incidence of CN in low-risk patients who underwent cardiac catheterization and received hydration and theophylline in comparison with hydration alone. A randomized, controlled, double-blind study by Huber et al  found similar results when they compared hydration versus hydration and theophylline in high-risk patients. Only 4% of patients in the theophylline group developed CN compared to 16% in the hydration group. However, other studies have not found any benefit in patients using theophylline for CN prophylaxis. As there were inconsistencies in dosing, administration regimens and definition of CN in the aforementioned studies, solid conclusions cannot be made. Although the above studies suggest benefit, theophylline is currently not recommended as a prophylactic agent for CN pending larger prospective trials.
Low-dose dopamine (0.5 to 3 mcg/kg/min) predominately activates DA-1 dopamine receptors, which causes intrarenal vasodilatation and increases renal blood flow.  Activation of the DA-1 receptor results in an increase in natriuresis and renal blood flow, whereas DA-2 activity results in vasoconstriction intrarenally.  The goal of dopamine therapy is to maximize DA-1 receptor effect and minimize DA-2 receptor activity. A randomized, prospective study by Abizaid et al  studied diabetic and non-diabetic chronic renal insufficiency patients who underwent cardiac catheterization. They received fluid hydration with 0.45% saline at 1mL/kg/h started 12 hours prior to and continued 12 hours after the procedure. The two experimental groups received dopamine (2.5 mcg/kg/min) plus saline or aminophylline (4 mg/kg followed by a drip of 0.4 mg/kg/ hour) plus saline. Fifty percent of patients who received dopamine and saline infusion developed CN, compared with only 30% of those who received saline alone. This difference was not significant in either the dopamine or aminophylline groups. The authors actually found dopamine to have a deleterious effect on the severity of renal failure, prolonging the course of the disease. There were several limitations to the current study that included a very sensitive definition of contrast-induced ARF, a small number of enrolled patients, and lack of information regarding fluid balance and body weight. Subsequent studies could not prove a protective effect of dopamine on prevention of CN.
Furthermore, selective activation of DA-1 receptors cannot be reliably achieved, there have been reports of "spillover stimulation" of alpha and beta adrenergic receptor contributing arrhythmias and other complications of acute renal failure. Also, many studies have found an increased incidence of nephrotoxicity in diabetic patients. Dopamine use cannot be yet advocated as prophylaxis for CN.
7. Endothelin receptor antagonists
Endothelin-1, a potent vasoconstrictor may have a role in the development of CN. A multicenter, double-blind, prospective study of 158 human patients comparing an endothelin antagonist to placebo failed to confirm these findings. All patients received hydration (1 ml/kg/h) prior to after contrast infusion. The incidence of CN was 27 % higher with endothelin blockade (p<0.05).
Fenoldopam is a modified dopamine that is selective DA-1 agonist without DA-2 or beta adrenergic stimulation as seen with dopamine. Fenoldopam induces renal vasodilatation and decreases renal vascular resistance, which increases medullary blood flow, glomerular filtration rate and urinary sodium, and water excretion. A recent literature review by Asif  analyzed five studies including. The data were inconclusive and did not support the use of fenoldopam as prophylaxis for CN. A large prospective clinical trial may resolve the issue.
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