Chapter 12. Contrast-Induced Nephropathy

• Rise of serum creatinine of ≥0.5 mg/dL or 25% above baseline within 48 hours after parenteral contrast administration.
• Majority of cases are nonoliguric.
• Peak in serum creatinine usually occurs within 3–5 days with complete resolution in 7–10 days for most patients.
• Oliguria and need for dialysis are unusual and are primarily seen in patients with diabetes with severe chronic kidney disease.

Contrast-induced nephropathy (CIN) is a common cause of hospital-acquired acute renal failure. Although the incidence of CIN is low, the number of patients receiving intravenous contrast media is enormous and is expected to rise as the population ages and greater numbers of patients will be subjected to diagnostic and therapeutic procedures requiring intravascular contrast.

Observational retrospective studies have demonstrated that patients incurring CIN had significantly higher in-hospital mortality than counterparts who did not develop CIN, particularly so if they went on to need dialysis. Multivariate regression analysis, adjusting for baseline differences in comorbidities, strongly suggests that CIN is, in fact, an independent predictor of mortality.

Various patient and procedural factors influence the likelihood of developing CIN. Among patient-related factors, preexisting chronic kidney disease (CKD) is regarded as the most potent risk factor. Nearly 60% of patients developing CIN have baseline CKD, and the incidence of CIN parallels the severity of prestanding renal impairment. Diabetes mellitus also confers increased risk of developing CIN, but only in patients with CKD. Thus the risk of CIN is greatest in patients with CKD and diabetes, lower in nondiabetic patients with CKD, and lowest in patients without preexisting CKD regardless of their diabetic status. Similarly, patients with CKD and diabetes are at the highest risk of developing oliguric acute renal failure and of requiring dialysis. Patients with CIN who require dialysis have a very high in-hospital mortality.

Volume depletion, congestive heart failure, older age, and hypotension have all been cited as risk factors for CIN but are probably primarily markers for a low glomerular filtration rate (GFR), the true risk factor. Concomitant use of nephrotoxins such as nonsteroidal anti-inflammatory agents also increase the risk for CIN.

Multiple myeloma has traditionally been considered a risk factor for CIN. However, recent studies using modern contrast agents indicate that patients with multiple myeloma are not at a greater risk, provided that they are volume replete at the time of contrast exposure.

Procedure-related factors will also influence the likelihood of CIN. Most studies, although not all, suggest that exposure to larger volumes of parenteral contrast causes greater predisposition to CIN. In addition, the type of contrast material (specifically its osmolality) influences the development of CIN. Contrast media formulations occur in three types: High-osmolar contrast media (also termed ionic), which have an osmolality of approximately 2000 mOsm/L, low-osmolar contrast media (also termed nonionic), which have an osmolality of 600–900 mOsm/L, and iso-osmolar contrast media (also a nonionic composition), which have an osmolality of 300 mOsm/L (Figure 12–1). Multiple studies in high-risk patients with CKD have demonstrated that low-osmolar contrast media results in less CIN than high-osmolar contrast media, and there is some evidence that iso-osmolar contrast media may be less nephrotoxic than low-osmolar contrast media.

Several mechanisms have been proposed to explain the pathogenesis of CIN. Measures aimed to prevent CIN (see Prevention below) are based on these pathogenetic mechanisms. Renal ischemia is currently considered the primary mechanism for CIN. It is known that the outer renal medulla has an extremely low oxygen tension (Po2 10–20 mm Hg), as the result of countercurrent oxygen exchange and removal between vasa rectae and utilization of oxygen by active tubular transport by the ascending loop of Henle. Administration of contrast media has been shown to selectively further reduce oxygen tension in this area of the kidney by a two-pronged mechanism. The first is reduction in renal blood flow, mediated by release of vasoconstrictive compounds such as endothelin and adenosine, an effect that is magnified by blockade of vasodilatory compounds such as nitric oxide and prostaglandins. The second is increased oxygen utilization caused by increased work of active transport in response to an osmotic diuresis induced by contrast media in the renal tubule. A summary of these effects is depicted in Figure 12–2.

Hyperosmolarity may itself be etiologic in the development of CIN. Intratubular hyperosmolality may activate tubuloglomerular feedback or increase intratubular hydrostatic pressure, either of which could reduce glomerular filtration. Hyperosmolality may also increase tubular cell apoptosis.

There is also evidence to suggest that generation of oxygen free radicals contributes to the pathogenesis of CIN. This theory would explain the possible ability of N-acetylcysteine (NAC), a free radical scavenger, and sodium bicarbonate, which inhibits the enzymatic formation of free radicals, to prevent CIN (see Prevention below).

Finally, there is evidence to suggest that contrast media cause direct cellular toxicity. Contrast media have been shown to cause proximal tubule cell vacuolization, interstitial inflammation, and cellular necrosis both in experimental animals and in isolated nephron segments.

Multiple preventive strategies for CIN have been studied (Table 12–1). A number of these have been proven to be ineffective in well-designed, randomized control trials. Among this group are diuretics, mannitol, dopamine, atrial natriuretic peptide, endothelin receptor antagonists, and fenoldopam. Other strategies have proven more successful and are discussed below.

Extracellular fluid (ECF) volume expansion has traditionally been considered the primary therapeutic intervention to prevent CIN. Correction of volume contraction with ECF expansion is expected to diminish vasoconstrictive responses that contribute to renal ischemia and decrease contact time and concentration of contrast media within the renal tubules. Early clinical studies using historic controls suggested a beneficial role for ECF expansion. Following these studies, volume expansion quickly became the standard of care, although no prospective, randomized, placebo-controlled studies have been conducted to evaluate its efficacy, probably for ethical concerns. Subsequent studies have attempted to delineate the best protocol for prophylactic ECF expansion, but to date, no consensus has been reached due to variability among studies in quality, size, subject selection, and endpoint definition. The limited literature suggests that intravenous volume expansion is superior to oral, that longer courses of parenteral fluid administration are superior to shorter courses, and that isotonic fluids are superior to hypotonic fluids.

NAC was first reported in the late 1990s to be a viable prophylactic strategy for CIN. The most commonly employed dose of NAC is 600 mg by mouth twice daily the day prior to and the day of contrast administration. Initially, this finding was greeted with widespread enthusiasm and the use of NAC quickly became common in clinical practice. Subsequent studies of its efficacy have been mixed, as have meta-analyses of those studies. To date, it remains uncertain if NAC is an effective preventative measure, but it is nonetheless often used in clinical practice, based on its safety, simplicity, and low cost.

Theophylline may also be effective in the prevention on CIN. Several studies have demonstrated that theophylline blunts the decrement in GFR following contrast exposure, possibly by inhibiting adenosine-induced renal vasoconstriction. However, none of these studies included high-risk patients nor has clinically significant CIN been observed in theophylline-treated subjects or controls. Therefore no conclusions can be made about its efficacy. It should be noted that theophylline carries the risk of precipitating ventricular arrhythmias, seizures, and other adverse effects, and these drawbacks must be factored into any decision regarding its use in CIN prophylaxis.

Reduction in contrast volume and osmolality are well-established and reliable means of diminishing the occurrence of CIN in high-risk azotemic patients. With regard to osmolality, clinical trials have established the superiority of low-osmolar over high-osmolar contrast media. Although initial clinical reports demonstrate lower nephrotoxicity with iso-osmolar versus at least one low-osmolar contrast media, the relative nephrotoxicity of iso-osmolar contrast media is still under investigation.

Although hemodialysis has largely been proven not to be an efficacious means of CIN prophylaxis, hemofiltration has been suggested to be effective. Unfortunately, limitations in study design do not allow the value of hemofiltration in this setting to be known for certain. Given the high cost and logistic difficulty associated with providing hemofiltration, this modality is unlikely to gain widespread clinical acceptance for CIN prophylaxis unless additional and better designed studies demonstrate its effectiveness.

Although initial reports showed a superiority of sodium bicarbonate over saline in the prevention of CIN, more recent publications suggest that the two modalities have equivalent prophylactic value. Additional studies are ongoing which may further clarify the question of whether sodium bicarbonate has any advantage compared to isotonic saline in this setting.

Symptoms and Signs

In the vast majority of patients with CIN, there are no symptoms or signs that would indicate the presence of this complication. In a smaller subset of affected patients, symptoms of oliguria with or without symptoms or physical findings of fluid overload may be present. Rarely, a patient with CIN may present with symptoms and signs of uremia.

Laboratory Findings

In the majority of patients with CIN, the serum creatinine value begins to rise within 24–48 hours after contrast media exposure, peaks within 3–5 days, and returns to baseline levels within 7–10 days. The majority of patients are nonoliguric and often have low urine sodium concentration.

In more severe cases of CIN, the serum creatinine may not peak until 5–10 days and may be accompanied by oliguria and a requirement for dialysis. Severe cases of CIN are more often (though not exclusively) seen in patients with advanced CKD, particularly those with coexisting diabetes mellitus.

The urinalysis in patients with CIN typically demonstrates coarse granular casts, renal tubular epithelial cells, and amorphous debris, findings characteristic of acute tubular necrosis.

Imaging Tests

Renal imaging is not helpful in confirming the diagnosis of CIN, but may be undertaken to exclude other causes of acute renal failure (ie, renal ultrasound to obstructive nephropathy).

Renal atheroembolism as a cause of acute renal failure following contrast exposure needs to be distinguished from CIN. This complication may arise in any patient who receives contrast media through an arterial route, regardless of whether the contrast was administered for a diagnostic procedure or for an interventional therapeutic indication. Renal atheroembolism is suggested when the rise in serum creatinine begins more than 48 hours after contrast exposure but can also present within 48 hours following contrast administration. On physical examination, the physician should look for livedo reticularis, digital ischemia (purple/blue toe syndrome), retinal embolization (Hollenhorst plaque), or other signs of systemic embolization, which would suggest atheroembolism. Patients with atheroembolism may demonstrate urine or peripheral blood eosinophilia and/or hypocomplementemia on laboratory analysis, abnormalities not found with CIN.

Since contrast media are commonly administered to hemodynamically unstable patients, the possibility of ischemic acute tubular necrosis in the differential of acute renal failure following contrast exposure must be considered. Clinically, acute renal failure from ischemia may be difficult to impossible to distinguish from CIN.

Other diagnoses to consider are allergic interstitial nephritis (since many contrast-exposed patients will be hospitalized and receive new medications), which usually presents with some combination of fever, rash, peripheral blood eosinophilia and sterile pyuria, and obstructive nephropathy, which is suggested by a bsent to low urine output and hydronephrosis seen on renal imaging.

There is no specific therapy for CIN once it occurs. The best strategy is one of prevention. Preemptive nephrologic consultation to ensure that optimal prophylactic strategies are provided may be of value in certain high-risk azotemic patients.

Once a patient develops CIN, care should be taken to judiciously manage fluid and electrolytes and adjust medications that are renally eliminated. Regular monitoring of electrolytes, blood urea nitrogen (BUN), and creatinine is recommended since it is not possible to predict which patients with CIN will have a short, transient, and asymptomatic course of acute renal failure or demonstrate more clinically severe acute renal failure. Patients developing oliguria, severe electrolyte or acid–base abnormalities, or volume overload may require hemodialysis. Patients with advanced CKD, particularly those with diabetes mellitus, are most likely to require dialytic support.

Complete recovery of renal function usually occurs in patients affected with CIN. A small minority of patients may go on to require chronic renal replacement therapy while others may be left with residual renal injury but not require dialysis. Patients in the former group invariably have severe CKD prior to contrast administration. The proportion of patients who develop sustained, subclinical decrements in GFR is unknown.

In recent years, multiple studies have suggested that in-hospital mortality is significantly higher in patients developing CIN after contrast exposure than those without this complication. Mortality appears to be highest in those patients with CIN who require hemodialysis. Methodologic limitations of these studies do not allow a definitive conclusion as to whether the higher mortality seen in these patients is due to CIN per se or other comorbidities more commonly seen in the patients affected with CIN.