1. What is contrast-induced nephropathy (CIN), and how does it occur?

Iodinated contrast media can lead to a usually reversible form of non-oliguric acute kidney injury (AKI) that occurs typically 24 to 48 hours after intravenous (IV) or intra-arterial administration of contrast. CIN does not occur with oral delivery of contrast media because contrast is not absorbed through the gut. Contrast media causes AKI through two major mechanisms: (1) renal vasoconstriction causing ischemia, and (2) direct tubular epithelial toxicity from the contrast. After contrast administration, there is an immediate transient increase in renal blood flow followed by a prolonged period of reduced flow resulting in renal ischemia. Contrast media stimulates the release of vasoconstrictive mediators, such as endothelin, while blocking the release of vasodilators, such as prostaglandins and nitric oxide, which causes hypoperfusion. The renal medulla, which is poorly oxygenated in normal conditions, is susceptible to injury from contrast-induced reductions in oxygen delivery. This ischemic injury generates reactive oxygen species, which causes tubular injury by affecting renal endothelial cells. Furthermore, contrast agents are directly toxic to renal epithelial cells, causing proximal tubular vacuolization, interstitial inflammation, and cellular necrosis.

2. What is the typical clinical presentation of atheroembolic acute AKI? What is the differential diagnosis for kidney failure following cardiac catheterization?

The differential diagnoses of kidney failure following cardiac catheterization includes ischemic acute tubular necrosis, cardiorenal syndrome, renal atheroemboli/cholesterol emboli syndrome, and prerenal causes of AKI. The presence of diffuse atherosclerosis predisposes a patient to renal atheroemboli, which is characterized by a stair-step pattern to the increase in creatinine that occurs days to weeks after the procedure with little or no recovery of kidney function. Other distinguishing features of atheroembolic acute AKI are the presence of embolic lesions (as on the toes and fingers), livedo reticularis, transient eosinophilia, hypocomplementemia, vague abdominal pain (due to small vessel ischemic disease), and Hollenhorst plaques (cholesterol emboli to retinal vessels).

3. What is the clinical significance of CIN?

CIN is defined as an increase in the pre-contrast baseline serum creatinine within 48 to 72 hours following contrast administration. Most studies have defined CIN as an elevation of serum creatinine of >0.5 mg/dL or >25% of baseline value. Some studies now define using the AKIN criteria of >0.3 mg/dL. CIN has been shown to be associated with an increase in hospital and long-term morbidity and mortality. It is noted as the third leading cause of AKI for inpatients with retrospective studies showing its incidence varying between 3% and 30% depending on contrast volume, concomitant risk factors, and whether the contrast is given intravenously or arterially. Lower incidences are seen with venous administration. The in-hospital mortality rates in a large retrospective analysis were 1.1% without CIN, 7.1% in CIN not requiring dialysis, and 35.7% for those with CIN requiring dialysis; fortunately, CIN requiring dialysis is rare (typically representing less than 2% of CIN). Although CIN is usually reversible and rarely requires renal replacement, studies have shown that CIN requiring dialysis has a 2-year survival rate of less than 40%. This high mortality rate is difficult to interpret and difficult to solely contribute to CIN, as these patients tend to have confounding comorbidities that also place them at higher mortality risk. CIN also has been shown to be an independent risk factor for subsequent chronic kidney disease (CKD), as noted in many retrospective studies. There has been an association between CIN and mortality, but a causal relationship has never been truly established. Several retrospective studies have shown that less than one-third of patients with CIN will have some permanent loss of kidney function following an episode of CIN.

4. What are the risk factors for the development of CIN?

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  CKD: The main predisposing risk factor is preexisting kidney disease with serum creatinine ≥1.5 mg/dL or estimated glomerular filtration rate below 60 mL/min/1.73 m2. Furthermore, the more severe the degree of CKD, the greater the risk of CIN.

  
  
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  Diabetes: The presence of diabetes further enhances this risk; however, diabetes itself without kidney disease has not been associated with CIN.

  
  
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  Contrast volume: High doses of contrast are associated with increased risk. Several studies in percutaneous coronary intervention (PCI) patients have shown that low-volume contrast (<50 mL) during coronary angiography can be adequate for coronary artery visualization and stent placement, but they have not directly looked at the decreased rates of CIN. However, it would be expected—with minimal contrast volumes—that the incidence of CIN post-PCI would be either eliminated or mitigated.

  
  
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  Intra-arterial administration carries a higher risk of injury than does IV administration.

  
  
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  Advanced age

  
  
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  Proteinuria

  
  
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  Hypotension

  
  
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  Volume depletion

  
  
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  Congestive heart failure

  
  
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  Multiple myeloma (historical risk factor; unlikely a risk factor with modern contrast agents)

  
  
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  Concurrent use of nonsteroidal anti-inflammatory agents

  
  
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  Renin-Angiotensin-Aldosterone System (RAAS) blockade*

  
  
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  Kidney transplant without CKD*

  
  
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  Cirrhosis*

* Synergistic risk factors; controversial data about true risk.

Although CIN has been described for years following IV contrast radiologic studies, large trials with propensity matching suggest that IV contrast media has had no statistically significant increase in AKI, dialysis, or mortality, compared to patients with similar procedures without contrast. Despite these findings, we still recommend that in high-risk patients (i.e., with impaired kidney function) scheduled for IV contrast radiologic studies, the usual prophylactic steps be followed (see later) to minimize risk and prophylactic techniques.

5. What are the clinical features and how the diagnosis is made?

CIN usually manifests with AKI developing within 24 to 48 hours, with peak injury anywhere between 72 and 120 hours after insult. It may take 7 to 10 days before serum creatinine returns to baseline. The injury typically does not cause proteinuria, and the urinalysis resembles acute tubular necrosis with muddy brown casts and renal tubular epithelial cells. The fractional excretion of sodium is typically below 1%, which presumably is due to the severe vasoconstriction, although the significance of this is confounded in that CIN is almost always non-oliguric. Kidney biopsy is not indicated unless the presentation is atypical and the diagnosis is unclear.

6. What prophylactic hydration measures are recommended?

Beyond supportive measures there are no treatments to reverse CIN once it is established, so prophylactic measures are the only intervention available. Prophylaxis should be used in high-risk individuals, primarily patients with impaired kidney function. Volume expansion is the only consistently effective prophylactic measure to reduce the risk for CIN. Volume expansion may work by:

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  Suppressing the renin-angiotensin system

  
  
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  Reducing vasoconstrictive mediators

  
  
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  Diluting the contrast media

  
  
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  Increasing the transit time of contrast media through the kidney

Pre-procedure hydration has been done with a variety of fluids, including oral hydration, hypotonic solutions (0.45% Normal Saline), and isotonic crystalloids (normal saline, Ringer’s lactate, and isotonic bicarbonate solutions). In a prospective trial, normal saline was superior to 0.45% saline. This is expected because the isotonic fluid provides more effective volume expansion. IV hydration is recommended over oral hydration for the same reason. Until recently, isotonic bicarbonate was suggested to be a better prophylactic solution than normal saline possibly by reducing reactive oxygen species formation. However a large study (4993 patients) comparing isotonic bicarbonate to normal saline has now been completed (PRESERVE Trial) and did not show any benefit of isotonic bicarbonate over normal saline. Thus, the former should not be used due to lack of benefit, increased cost, and risk of compounding errors.

Our recommended infusion rate is:

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  Outpatient: 3 mL/kg/hr for 1 hour pre-contrast administration and 1 to 1.5 mL/kg/hr for 4 to 6 hours after contrast

  
  
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  Inpatients: 1 mL/kg/hr for 6 to 12 hours pre-procedure and intra-procedure, and 6 to 12 hours post-procedure

Infusion rates may need to be reduced in patients at risk for heart failure. The safe administration of prophylactic fluids in these patients may be done by monitoring left ventricular end-diastolic pressures, which was shown to be an effective measure in reducing CIN in the POSEIDON trial.