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Year : 2013  |  Volume : 1  |  Issue : 2  |  Page : 39-45

Contrast induced nephropathy: Pathophysiology and prevention

1 Department of Cardiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
2 Department of Cardiology, Heritage Hospital, Varanasi, Uttar Pradesh, India

Date of Web Publication21-Sep-2013

Correspondence Address:
Sudarshan Kumar Vijay
Department of Cardiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti khand, Gomti Nagar, Lucknow - 226 010, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2321-449x.118580

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The steadily increasing use of contrast media in radiological and interventional cardiac procedures has led to more research and well designed studies of prophylactic strategies for its leading life threatening side effect of contrast induced nephropathy (CIN). CIN adversely affects the prognosis after interventional procedure and poses substantial extra burden on health care costs. The importance of understanding of CIN lies in the fact that no available treatment can reverse or ameliorate it once it develops, but prevention is possible. Herein, we discuss the detailed pathophysiological aspects, risk factors, proposed risk prediction algorithms and various prophylactic strategies for contrast induced nephropathy.

Keywords: Acute kidney injury,contrast induced nephropathy,prevention

How to cite this article:
Vijay SK, Tiwari BC, Singh AK. Contrast induced nephropathy: Pathophysiology and prevention. Heart India 2013;1:39-45

How to cite this URL:
Vijay SK, Tiwari BC, Singh AK. Contrast induced nephropathy: Pathophysiology and prevention. Heart India [serial online] 2013 [cited 2021 Mar 5];1:39-45. Available from: https://www.heartindia.net/text.asp?2013/1/2/39/118580

  Introduction Top

The contrast induced acute kidney injury (CIAKI) or more commonly known as contrast induced nephropathy (CIN) is a well-known cause of acute renal failure in a hospital setting. [1] It has a low incidence in general population [2] (2%), but there are certain at risk groups in which it is more common. The incidence of CIAKI also varies among reported studies in the literature and it is dependent on baseline risk factors, patient population and the criteria used for definition of CIN. The typical time course of CIAKI is increase in serum creatinine (SCr) occurring within the first 24 h after contrast exposure and peaking up to

5 days afterwards. The most commonly used definition of CIAKI is an increase in SCr concentration of at least 0.5 mg/dL or at least 25% from the baseline, within 48-72 h after exposure to contrast media (CM). [3],[4],[5] The AKI Network has proposed the definition of: An abrupt (within 48 h) reduction in kidney function, evidenced by an increase in the SCr concentration of at least 0.3 mg/dL or at least 50% from baseline or a reduction in urine output (documented oliguria of δ0.5 mL/kg/h for δ6 h). [6],[7] The frequency of contrast induced nephropathy has decreased in the past decade from from a general incidence of 15 to 7% [8] and this reduction occurred because of better prophylactic measures and refined iodinated CM with less renal toxicity. The CIN carries an in hospital mortality rate of δ20% and loss of renal function may persist over time. [9],[10] Even after adjusting for comorbid disease, patients with contrast-induced nephropathy had a 5.5-fold increased risk of death. [9] It has been shown that in-hospital mortality rates were 1.1% for patients with no CIN compared with 7.1% for those with nephropathy alone, and up to 35.7% for those with nephropathy requiring dialysis [11] and by 2 years, the mortality rate in patients who required dialysis was 81.2%. The need for dialysis after CIN varies according to individual patient risks at the time of contrast administration but is generally less than 1%. In other studies CIN developed in almost 4% of patients with underlying renal impairment [12] and 3% of patients undergoing primary percutaneous coronary intervention (PCI) for acute coronary syndromes. [13]

  Pathophysiology Top

At present our understanding of pathophysiology of CIAKI is still incomplete but the multiple pathways [Figure 1] that are shown to be involved include alteration in renal hemodymamics with vasoconstriction, renal ischemia with hypoxia, altered rheological properties due to osmolarity of CM affecting renal milieu and tubuloglomerular feedback, various autocrine and paracrine factors, and direct cellular toxicity of CM.
Figure 1: Different pathophysiological pathways in the development of contrast induced AKI

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  1. Vasoconstriction: Many neurohormonal and locally produced substances can mediate vasoconstriction. The experimental observation has suggested that endothelin plays a critical role in contrast induced vasoconstriction. [14] A randomized clinical trial of endothelin receptor antagonists (ERAs) or placebo in patients of chronic kidney disease undergoing angiography; however, showed the surprising results in which incidence of CIN was higher in ERAs group. [15] Adenosine also plays an important role in regulation of renal hemodynamics. Activation of A2 receptors causes vasodilatation of efferent arteriole and medullary capillaries and A1 receptors stimulation causes afferent arteriole vasoconstriction which predominates over vasodilatation and thus intravenous infusion of adenosine has been shown to decrease renal blood flow. [16] Theophylline is an adenosine nonselective receptor antagonist and it inhibited CM induced renal vasoconstriction. [16] The stimulation of rennin-angiotensin system and adrenergic activation does not appear to be involved in pathogenesis of CIAKI. [17],[18] Cortical vasoconstriction or preglomerular vasoconstriction is an important cause of CM induced reduction in glomerular filtration rate (GFR). [19],[20] The cortical vasoconstriction can also produce medullary blood flow as descending vasa reacta (DVR) arises from efferent arterioles and that is many source of blood to medulla. The medullary perfusion comprises of δ10% of total renal blood flow so cortical hyoperfusion plays a critical role in contrast mediated vasoconstriction. [21]
  2. Renal ischemia and hypoxia: In experimental models of CIAKI, the kidneys show pathologic ischemic changes with necrosis of thick ascending limbs as well as tubular collapse specially in the outer medulla. [22] After a transient increase in renal blood flow, contrast induces overall ~50% sustained reduction in renal blood flow that persists for several hours. Renal medullary hypoxia has a major role in the pathogenesis of CIAKI. Even in the normal circumstances, oxygenation in the renal medulla is poor, making it more vulnerable to hypoxia. The oxygen requirements are high in the medulla due to salt reabsorption in the thick ascending loop of henle, while oxygen delivery is poor. The low oxygen supply is due to greater distance between DVR that supply the blood to outer medulla. The CM further aggravates the oxygen demand-supply mismatch. The hyperosmolar contrast agents induce osmotic diuresis that causes increased work in the active transport of molecules and low oxygen tension is more aggravated by vasoconstriction. It has also been shown that CM reduces oxygen tension in both medulla as well as the renal cortex.
  3. Increased oxidative stress: The renal ischemia induces the formation of reactive oxygen species (ROS) which causes the disbalance between vasodilatory nitric oxide and vasoconstrictive free radicals and initiates the vicious cycle of vasoconstriction and more generation of ROS. Nitric oxide bioavailability in vasa reacta is reduced by CM and free radical such as superoxide concentration is increased. [23] The CM promotes endothelial cell death [24] by apoptosis and that leads to further decrease in nitric oxide synthesis. The pathophysiological role of adenosine in CIN is also explained by its tendency to generate ROS. [25] The major role of N-acetyl cysteine and sodium bicarbonate in prevention of CIN is because of its ability to mitigate the oxidative stress.
  4. Direct cellular toxicity of CM: The direct cytotoxic effects of CM may rely on iodine which has been shown to have toxicity on human cells and bacteria. Iodine can be released from CM by photolysis. [26] The rate of photolysis of CM is influenced by the storage time and exposure to light. A number of experimental studies has shown that CM can cause cell membrane damage, proximal cell vacuolization, interstitial inflammation, cellular necrosis, and enzymuria. [14],[18] The stasis of contrast in kidney allows cellular toxicity and death of renal tubular cells. Hyperosmolar solutions result in cell shrinkage and also influence the shape and size of erythrocytes; thus hampering their passage through narrow vessels, which creates renal hypoperfusion.
  5. CM properties: A direct positive correlation has been shown between osmolality of CM and nephrotoxicity. Using low osmolar contrast (osmolalities: 400-800 mosmol/kg H 2 O) in comparison to Hyperosmolar contrast solutions (osmolalities 1000-2500 mosmol/kg H 2 O) results in reduced incidence of CIAKI. [27] As water is reabsorbed along the length of tubule, CM becomes concentrated with its passage, which increases tubular fluid osmolality. The highly viscous CM have a prolonged contact time with the tubular epithelial cells, and accordingly tubular damage is greater, as indicated by biomarkers. [28] The ionic CM (iothalamate, diatrizoate, and metrizoate) have high osmolality and require two osmotically active particles to deliver three iodine atoms. Nonionic CM (iopromide, iohexol, ioversol, and iopamidol) have low osmolality as they require only one osmotically active particle to deliver three iodine atoms. The ioxalate is an ionic dimmer which has osmolality of 600 mosmol/kg, similar to low osmolar CM. The newer contrast agent iodixanol is a nonionic dimmer in which six iodine atoms are attached to one osmotically active article and thus it is iso-osmolar with plasma (300 mosmol/kg of H 2 O).

  Risk Factors For Cin Top

The various risk factors have a causative role in the development of contrast induced acute kidney injury and many of the indicators of risk are nonmodifiable [Figure 2].

  1. Baseline renal dysfunction: Preexisting renal insufficiency is the single major risk factor for CIAKI. Baseline renal filtration function is a surrogate marker for reduced nephron mass and renal parenchymal function. The risk of CIN is increased in patients with an estimated GFR (eGFR) of <60 mL/min/m 2 of the body surface area. The approximate percent risk of CIN can be calculated by multiplying SCr concentration in mg/dL by 10.
  2. Diabetes mellitus: The risk of developing CIN in diabetic patients is greater when diabetic nephropathy or baseline renal insufficiency is present. The need for dialysis in this group of patients who progress to CIN is greater as they commonly develop oliguria. [29] Proteinuria is also an important risk marker for development of CIN.
  3. Volume of CM: Various studies have a positive correlation between volume of CM injected and risk of development of CIAKI. [30],[31] In a multivariate analysis, the only significant factor associated with CIN was the CM volume, and the risk doubled with every 20 mL of CM. [31]
    Figure 2: Risk factors for contrast induced nephropathy (CIN)

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    A predetermined formula based on body weight and baseline renal function to limit the volume of CM in patients undergoing coronary angiography is 5 mL of contrast per kg of the body weight with maximum of 300 mL divided by SCr concentration in mg/dL. [32]
  4. Hemodynamic instability: A large series of PCI patients have shown an association between CIN and indicators of hemodynamic instability such as periprocedural hypotension and use of an intra-aortic balloon pump. [33],[34] Hypotension significantly increases risk of CIN as it causes renal ischemia. Advanced age, hypertension, nephrotoxic drugs, gout, volume depletion, and hyperviscous states (multiple myeloma) are other risk factors for development of CIAKI.

    The effect of risk factors is additive and the likelihood of CIN increases as the number of risk factor increases. A number of CIN risk prediction models have been proposed the best known being of Mehran et al., [35] [Figure 3]. In this risk prediction score, a number of clinical variables related to age, hemodynamic instability, diabetes, and eGFR are summated yielding an integer score that is directly related to risk of CIN and hemodialysis. A score ≤5 is associated with a risk of CIN of ≤7.5% and a risk of dialysis of 0.04%. In contrast, a score ≥16 is associated with ≥50% likelihood of CIAKI, and a risk of dialysis of over 12%.
Figure 3: CIN risk prediction model (Mehran et al.). Adapted from Journal of American College of Cardiology

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  Prophylactic Strategies Top

Currently many preventive measures have been tried which affect different pathogenetic mechanisms of CIN, but only few have shown real efficacy. The measures which failed to show any benefit in well-designed trials include dopamine, diuretics, atrial natriuretic peptide, fenoldopam, endothelin receptor antagonists, and L-Arginine.

The strategies that have proven or possible value are discussed here:

  1. Selection of CM: Over several few years CM have been refined to lower osmolalities levels. Red blood cell deformation, systemic vasodilation, intrarenal vasoconstriction, as well as direct renal tubular toxicity are all more common in contrast agents with osmolality greater than that of blood (>300 mosmol/kg). In a meta-analysis of studies before 1992, the pooled odds ratio (OR) for the incidence of CIN events (rise in SCr of >0.5 mg/dL in 25 trials was 0.61), 95% confidence interval (CI) 0.48-0.77, indicating a significant reduction in risk with low osmolar CM compared with that seen with high osmolar CM. [27] The other studies supported this finding subsequently. Iodixanol has the lowest risk of CIN in diabetes and chronic renal insufficiency. [36],[37] In a meta-analysis of 16 head-to-head, randomized trials (2,727 patients) of intra-arterial contrast medium, the incidence of CIN was significantly lower with iodixanol than with low osmolar CM. [38] Iotrolan is an another iso-osmolar contrast agent that is associated with lower incidence of CIN, but it is not approved for intravascular use. The American College of Cardiology/American Heart Association guidelines for the management of acute coronary syndromes patients with CKD listed the use of iso-osmolar contrast as a class I, level of Evidence: A recommendation.

    The volume of CM is also a significant risk factor for CIAKI and even small volumes of CM can have detrimental effects in persons at high risk. As a general rule, the volume of contrast received should not exceed twice the baseline level of eGFR in milliliters. [39] In patient with CKD a diagnostic catheterization should plan to use <30 mL of contrast, and if followed by PCI then <100 mL should be a reasonable goal.
  2. Volume expansion: Hydration has a main role in the prevention of CIN. There are limited data on the most suitable choice of intravenous fluid, but the evidence indicates that isotonic crystalloid (saline or bicarbonate solution) is probably better than half-normal saline. [40] The largest trial to date showed no benefit of sodium bicarbonate over normal saline. [41] The bicarbonate prevents CIN by shutting production of free radicals, but as it is absorbed in the proximal tubule, the medullary bicarbonate concentration remains low. Different regimens of saline hydration have been used, but no one regimen has demonstrated clear superiority. In one study isotonic saline had significantly low incidence of CIN when compared to half isotonic saline. [40] The overnight hydration is not shown to be better than brief intravenous hydration in patients of CKD. [42] There is no clear guideline or evidence for optimal rate and duration of infusion. Good urine output (>150 mL/h) in the 6 h after procedure is associated with decreased rate of CIN. [43] In order to achieve a urine flow of >150mL/h ≥1.0 to 1.5 mL/kg/min of intravenous fluid has to be administered for 3-12 h before and 6-12 h after contrast exposure. The oral hydration is not shown to be as effective as intravenous hydration. [42] Osmodiuretics have a stronger diuretic effect than saline, yet previous trials indicate that osmodiuretic mannitol accentuates rather than to prevents CIN. [43],[44] By increasing the urine output diuretics counteracts extracellular volume and thus furosemide and other agents promote CIN. However, when volume contraction is counterbalanced by volume supplementation furosemide and other diuretics may prove effective in preventing CIN, as recently described by two clinical trials. [45],[46] Utilizing a novel servocontrol device, the rate of intravenous saline infusion was adjusted to match the urine output, thus providing volume expansion even in the face of furosemide-forced diuresis. This procedure significantly reduced the CIN incidence in patients with chronic kidney disease [46] as well as in high-risk patients. [45]
  3. Pharmacologic measures: Currently there is no drug which is approved for the prevention of CIN, but there are certain pharmacologic agents which have been tested in trials and deserve further evaluation, like N-acetyl cysteine (NAC), statins, ascorbic acid, aminophylline/theophylline, and prostaglandin-E1. The ascorbic acid was tested in a multicentric placebo controlled trial in doses of 3 g orally night before and 2 g twice a day after procedure and has shown reduction in incidence of CIAKI. [47]

    N-acetyl cysteine is an antioxidant that has not been shown to be consistently effective in reduction of CIN, in trials. N-acetyl cysteine reduces skeletal muscle creatinine production; and thus, falsely appear to lower creatinine and not fundamentally prevent CIN. In one trial of primary percutaneous intervention, NAC lowered the rates of CIN. [48] The REMEDIAL (Renal Insufficiency Following Contrast Media Administration) trial showed that a combination of NAC and volume expansion with sodium bicarbonate was more effective than NAC alone. [49] Although NAC is safe and effective, its value in preventing CIN remain controversial.

    The data regarding theophylline use are mixed and favorable studies had limitations of small sample size, absence of high risk patients, and failure to show differences in the incidence of CIN. [50] Multiple studies have shown that statin reduce the rate of AKI during PCI and coronary artery bypass surgery (CABG). [51] Preservation of endothelial function at the level of the glomerulus and decrease in systemic inflammatory factors are postulated mechanisms by which statins may have renoprotective effects.

    Nonsteroidal anti-inflammatory drugs (NSAIDS) and other renotxic drugs should be discontinued prior to the procedure.
  4. Hemodialysis and hemofiltration: Several studies have shown that 2-3 h of hemodialysis removes 60-90% of the contrast medium. [52] However, the prophylactic value of hemodialysis in high risk patients, in preventing CIN has not been shown. In one study, hemofiltration significantly reduced CIN in high risk patients. [53] Hemofiltration works to ensure adequate intravascular volume, reduces uremic toxins that may worsen AKI, and provides stability to the high-risk patient after the procedure, reducing the risks of oliguria, volume overload, and electrolyte imbalance. Until the results of large randomized trials regarding efficacy of hemofiltration are available, it cannot be recommended as standard prophylaxis in every high risk patient.

  Novel Approaches Top

The need for a better marker of renal function than SCr is highly justified as SCr is an indirect and insensitive marker of kidney function. Neutrophil gelatinase associated lipocalin [54] and cystatin-C have demonstrated to be sensitive markers of early kidney injury and GFR, respectively.

Various novel approaches are in pipeline for prevention of CIN. Coronary sinus withdrawal of blood and contrast after intracoronary injection of contrast during coronary angiography, and thus reducing the amount of contrast delivered to kidneys, has been tested in experimental models. [55] Other strategies include use of intravenous antioxidants, forced hydration, and new less toxic contrast agents.

  Summary Top

CIAKI is commonly encountered in clinical practice due to increasing number of interventional cardiology and radiological procedures. CIN can occur due to multiple pathogenetic pathways which have a complex interaction with each other. Appropriate identification of individuals at high risk of CIN using risk prediction models is mandatory. An integrated approach [Figure 4] utilizing volume expansion, limiting amount of CM, use of novel isoosmolar contrast agents, and efficacious pharmacological intervention should be used to prevent the development of CIAKI.
Figure 4: Management protocol of patients receiving iodinated contrast media

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  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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