Contrast-Induced Nephropathy

Etiology

The most common cause of contrast-induced nephropathy is pre-existing chronic kidney disease. About 8% of patients with estimated glomerular filtration rate (eGFR) between 45 ml/min/1.73m2 to 60 ml/min/1.73m2, 13% of the patients with eGFR between 30 ml/min/1.73m2 to 45 ml/min/1.73m2, and 27% of patients with glomerular filtration rate (GFR) less than 30 ml/min/1.73m2 develop contrast-induced nephropathy following contrast exposure.[6][7][8] Other clinical factors include advanced age, diabetes, peripheral heart failure, females, peripheral vascular disease, hypertension, and a left ventricular ejection fraction (LVEF) of less than 40%. Precipitating factors include acute coronary syndrome, hypotension, volume depletion, concomitant nephrotoxic medications, and anemia.

Contrast media (CM) affect distinct anatomic sites in the kidney and manifest adverse effects via several mechanisms. They exert Four cardinal effects:

• A direct cytotoxic effect on the proximal tubules of the kidney
• Enhance cellular damage via reactive oxygen species
• Increase resistance to blood flow in the kidney
• Exacerbate renal vasoconstriction, particularly in the medulla which is especially important in patients with chronic kidney disease

There are several risk predictor models available to predict contrast-induced nephropathy risk before the procedure and the use of preventive measures. Gurm and colleagues used a cohort of over 68,000 percutaneous coronary intervention procedures to develop an online calculator risk predictor (http://bmc2.org/calculators/cin).

Similarly, the Roxana Mehran score predictor applies the following ten variables:

A risk score of less than 6 carries a risk of 7.5% and more than 16 carries up to 57% risk.

Epidemiology

The prevalence of diabetes and chronic kidney disease is rising. Both of these are risk factors for acute kidney injury after cardiac catheterization and percutaneous coronary interventions. Based on current definitions the incidence of contrast-induced nephropathy ranges from 2% to 30%. Most cases are completely reversible within two to four weeks. The need for renal replacement therapy is rare at a rate of 1% to 4%, and of these, less than 50% require long-term renal replacement therapy. The incidence of contrast-induced nephropathy is calculated to be more than 2% in the general population. However, in high-risk groups with risk factors for kidney disease, the incidence is as high as 20% to 30%. It is reported that there is a lower risk of contrast-induced nephropathy when low osmolar contrast media is used.[9]

Contrast-induced nephropathy is the third leading cause of iatrogenic acute kidney injury. The commonest cause is hypoperfusion of the kidneys causing either prerenal injury or acute tubular necrosis.[10] Moreover, the number and the type of risk factors directly affect the incidence of renal impairment. The incidence rate also depends on the procedure, with reports in the literature varying from 1.6-2.3% for diagnostic investigations to 14.5% overall in coronary intervention.[11] 

In patients older than 60 years, the incidence of CIN has been reported as 8%-16%. In patients with acute myocardial infarction who undergo coronary intervention, it has been shown that the age of 75 years or more is an independent risk factor for the development of CIN.

Pathophysiology

The pathophysiology of contrast-induced nephropathy remains unclear. The proposed theory is a combination of vasoconstriction, ischemia, hypoxia, and direct toxic effect on renal tubular cells. The hemodynamic alterations and medications can exacerbate the possibility of contrast-induced nephropathy. The risk of contrast-induced kidney injury is much higher with the arterial administration of contrast compared with venous administration of contrast. Metformin can cause lactic acidosis in the setting of kidney dysfunction and acute kidney injury. The FDA recommends holding metformin on the day of contrast exposure and 48 hours after the procedure. Another cause is catheter-induced aeroembolism to the renal microvasculature. Laboratory abnormalities may include eosinophilia and eosinophilia in an acute kidney injury as a result of cholesterol atheroembolism.[8]

Renal microcirculation depends on an interplay of hormonal, neural, paracrine, and autocrine signals. Of note are:

• The vasodilator - nitric oxide (NO)
• The vasoconstrictors - vasopressin, adenosine, angiotensin 2, and endothelins

Nitric oxide seems to be crucial, with antiplatelet, vasodilatory, anti-inflammatory, and antioxidant effects. The levels of asymmetrical dimethylarginine, which is an inhibitor of NO synthase, can be utilized as a marker of CIN, particularly in patients with adverse outcomes.

Contrast media-mediated vasoconstriction occurs as a result of a direct action of media on vascular smooth muscle and via metabolites such as endothelin and adenosine. Additionally, it decreases water reabsorption, causing an increase in interstitial pressure. This reduces GFR and compression of the vasa recta follows. These mechanisms contribute to aggravating medullary hypoxemia and vasoconstriction in the kidneys in patients who already have volume depletion.   Finally, contrast media also worsens resistance to blood flow by causing an increase in blood viscosity and by lowering red cell deformability. The ensuing intravascular sludging causes local ischemia and activation of reactive oxygen species leading to tubular damage at a cellular level.

Histopathology

When kidney biopsies are done, there is visible evidence of direct damage to the renal tubular epithelial cells by the contrast dye. One may note the presence of interstitial inflammation, cell vacuolization, and patch necrosis. This damage to the cells is usually evident within the first 7-10 days of the injury.

Direct toxic effects of contrast media on tubular epithelial cells are characterized by the following:

• Cell vacuolization
• Interstitial inflammation
• Cellular necrosis

These characteristic changes, known as osmotic nephrosis, were noted in 22.3% of patients in a study. These patients underwent renal biopsy within 10 days of contrast exposure.[12]

History and Physical

Contrast-induced nephropathy was first reported by Bartel et al. in the 1950s and was related to a fatal acute renal injury that happened following intravenous pyelography in a patient with a myeloma kidney. A transient rise in creatine occurs in 15% of patients undergoing invasive procedures. Even mild contrast-induced nephropathy is associated with longer hospital stays, increased cost, and higher short-term and long-term mortality. The reported incidence varies between 7% and 11% depending on the definition applied, study population, and setting. An average additional cost of more than $10,000 is associated with a contrast-induced nephropathy-related hospital stay. Contrast-induced acute kidney injury is diagnosed by following up on creatinine levels two to three days after contrast exposure.

Patients suffering from contrast-induced nephropathy usually have a preceding history of contrast administration, 24-48 hours before the presentation, while undergoing a diagnostic or therapeutic procedure, such as percutaneous coronary intervention. Acute kidney injury is mostly nonoliguric.

A physical examination is helpful in ruling out other possible causes of acute nephropathies, for instance, cholesterol emboli (pathognomonic findings of which are blue toes and livedo reticularis) or interstitial nephritis secondary to drugs (that typically involves a rash). There may be signs of volume depletion or there could be decompensated heart failure.

Evaluation

Contrast-induced nephropathy is defined as a rise in serum creatinine of at least 0.5 mg/dL or a 25% increase from baseline within 48 to 72 hours after contrast exposure. The Kidney Disease Improving Global Outcome (KDIGO) definition is different, with stage 1 being a rapid rise of creatinine to greater than 0.3 mg/dL within 48 hours or the relative rise of 50% or more from baseline in 7 days or less or a reduction in urine output to less than 0.5 ml/kg/hr for 6 to 12 hours. This severity is further staged based on creatinine levels, urine output, or the need for renal replacement therapy.[13]

In contrast-induced nephropathy, serum creatinine usually begins to rise within 24 hours after the administration of contrast media, peaks between 3 and 5 days, and comes back to baseline in 7-10 days. A surrogate marker of renal function, serum cystatin C, is increased in patients with contrast-induced nephropathy.

Nonspecific formed elements may appear in the urine, such as tubular epithelial cells, granular casts, uric acid crystals, and debris. However, they do not have a correlation with severity.

It is worthwhile to do urine osmolality that tends to be less than 350 mOsm/kg. The fractional excretion of sodium (FENa) may vary a great deal. In a small number of patients with oliguric CIN, FENa is low earlier in the course, despite the absence of clinical signs of volume depletion.

Treatment / Management

The most common strategy to reduce the risk of contrast-induced nephropathy must be considered before the contrast exposure. Periprocedural hydration in chronic kidney disease patients by initiating intravenous (IV) fluid with 0.9% normal saline infusion at a rate of 1 ml/kg/hr for 6 to 12 hours before the procedure and continuing after the procedure. Some literature supports a sliding scale IV hydration protocol based on left ventricular end-diastolic pressure. 

Bicarbonate alkalinizes the renal tubular fluid preventing free radical injury. Bicarbonate, by alkalinizing the environment, slows down that reaction Harber-Weiss reaction which otherwise would have resulted in free radical injury. It also helps to scavenge reactive oxygen species from NO, such as peroxynitrite.

Bicarbonate is most often given as an infusion of sodium bicarbonate at a rate of 3 mL/kg/hour an hour prior to the procedure, to be continued at a rate of 1 mL/kg/hour for six hours. However, the exact duration remains a matter of debate. According to some studies, hydration with sodium bicarbonate is more protective than normal saline alone.

In a clinical trial, there was no consistent benefit to justify the routine administration of sodium bicarbonate in patients undergoing cardiac catheterization. Similarly, the Acetylcysteine for Contrast-Induced Nephropathy trial found no difference between acetylcysteine and placebo in the prevention of contrast-induced neuropathy or need for dialysis.

It is reasonable to pretreat patients with high-intensity statin before contrast use. A meta-analysis observed that pretreatment with rosuvastatin could significantly decrease the incidence of contrast-induced nephropathy (OR 0.49, P less than 0.001). However, rosuvastatin did not appear to be effective for the prevention of contrast-induced nephropathy in patients already suffering from chronic kidney disease undergoing elective cardiac catheterization.[14](A1)

Fenoldopam, a dopamine receptor agonist, did not have any benefit in clinical trials. Ascorbic acid 1 g to 3 g for one to three days periprocedural has been shown to reduce contrast-induced neuropathy by 33%. The benefit of hemofiltration has been demonstrated in an isolated trial. During the procedure, one can use a smaller guide catheter, minimize contrast use, avoid ventriculogram, biplane coronary angiography, low osmolar, or iso-osmolar nonionic contrast agent, and maximum allowable contrast dose to be three times the estimated GFR.[15][16][17]

Differential Diagnosis

Following are some important differential diagnoses that need to be considered while making a diagnosis of contrast-induced nephropathy:

• Acute renal failure
• Embolic renal disease
• Interstitial nephritis
• Acute tubular necrosis
• Renal artery stenosis

Staging

Several scoring systems have been developed to predict contrast-induced kidney injury and the following are the risk factors:

• Use of an intra-aortic balloon pump
• Congestive heart failure (CHF)
• Hypotension
• Elevated creatinine (More than 1.5)
• Age greater than 75
• Diabetes
• Anemia
• Use of contrast volume more than 100 ml

Prognosis

Overall, the prognosis depends on patients' co-morbidities including but not limited to baseline renal function. Depending upon the scoring system, following contrast administration, there can be a probability of CIN. Generally, it is reversible and biopsy is rarely needed for the diagnosis.

CIN is normally a self-resolving process, with renal function getting back to normal within 7-14 days of the administration of contrast. Fewer than one-third of patients develop some level of residual renal impairment.

Renal replacement therapy is required in less than 1% of the cases, with a slightly raised incidence in patients who are either having an underlying renal impairment (3.1%) or undergoing primary percutaneous coronary intervention for myocardial infarction (3%). However, in patients suffering from diabetes and severe kidney failure, the rate of dialysis may be as high as 12%.   18% of CIN patients who require dialysis end up needing it permanently. However, the majority of these patients have severe renal insufficiency and coexisting diabetic nephropathy. They would have progressed to requiring dialysis regardless of the development of CIN.   There is a growing understanding that AKI after contrast media exposure can be an indicator of CRF or ESRF. In an observational study, 3986 patients were included in which coronary angiography was performed, 12.1% of patients developed contrast-induced AKI, and of those, 18.6% sustained permanent renal damage.[18]

Patients who need dialysis have a worse prognosis, with 35.7% inhospital mortality reported (compared to 7.1% in the nondialysis cohort) and 2-year survival of only 19%.

In a study on the long-term mortality associated with CIN after PCI in patients with or without CKD, CIN was observed to be significantly linked with long-term mortality in the whole group (hazard ratio 2.26, 95% confidence interval 1.62 to 2.29, P value less than 0.0001) and in patients having CKD (hazard ratio 2.62, 95% confidence interval 1.91 to 3.57, P value less than 0.0001) but not in patients without CKD (hazard ratio 1.23, 95% confidence interval 0.47 to 2.62, P is equal to 0.6). The occurrence of CIN in patients with CKD was found to be 11% and 2% in patients without CKD.[19]

Complications

Following are the complications that are associated with contrast-induced nephropathy:

• Acute renal failure
• Acute on chronic renal failure
• Hypersensitivity reactions
• Fluid overload
• Pulmonary edema
• Contrast-induced thyroid dysfunction