An Overview of Contrast-Associated Acute Kidney Injury Following Lower-Extremity Percutaneous Peripheral Interventions

Abstract: Contrast-associated acute kidney injury, resulting from the use of iodinated contrast media, is a well-known adverse event following endovascular procedures and is associated with poor prognosis when it happens. There is an abundance of literature studying acute kidney injury following percutaneous coronary interventions, with very few studies done in the setting of percutaneous peripheral intervention. Although both percutaneous coronary intervention and percutaneous peripheral intervention utilize iodinated contrast media, several differences exist that can affect the incidence and management of contrast-associated acute kidney injury. This article aims to review what we currently know about contrast-associated acute kidney injury and available prevention strategies, specifically following percutaneous peripheral interventions.

Reprinted with permission from J INVASIVE CARDIOL 2020;32(7):276-282. 

Key words: contrast-associated acute kidney injury, contrast-induced nephropathy, endovascular procedures, iodinated contrast media, percutaneous vascular intervention

Iodinated contrast media (ICM) is widely used for invasive cardiovascular procedures. The administration of ICM is linked to the development of contrast-associated acute kidney injury (CA-AKI). Most of the research on CA-AKI has been performed in the setting of coronary interventions (PCI), with fewer data available in the setting of percutaneous peripheral vascular intervention (PVI). The incidence of CA-AKI for patients undergoing PVI ranges from 3%-10% according to several published studies.^1-3 The rate of CA-AKI appears to be related to patient comorbidities and the clinical presentation; for example, claudication vs critical limb ischemia (CLI).^1,2 Due to the lack of robust data and specific guidance from many major professional societies, CA-AKI continues to pose a challenge for cardiologists when planning for PVI. The majority of preventive strategies are extrapolated from CA-AKI studies in the setting of PCI; whether these interventions are equally applicable to PVI remains to be further elucidated. We therefore review what is currently known about CA-AKI as well as potential preventive measures during PVI.

Overview of the Pathophysiology and Definitions of CA-AKI

Despite decades of recognizing the impact of percutaneous interventions on renal function, the exact mechanisms of CA-AKI remain poorly understood. Renal medullary hypoxia seems to be a key derangement in the pathogenesis of CA-AKI. This process is theorized to be caused by direct cytotoxicity of ICM. The subsequent release of renal vasoconstrictors, such as adenosine, vasopressin and prostaglandin E2, leads to reduced blood flow, medullary hypoperfusion, and hypoxia. The increases in renal oxygen demand, endothelial dysfunction, and reduction of nitric oxide production all contribute to the renal injury seen in CA-AKI. The increased renal blood viscosity caused by ICM may also play a role in CA-AKI physiology.⁴ As ICM becomes more concentrated in the medulla due to renal physiology, the increase in ICM concentration in the medulla leads to increased viscosity and poor renal blood flow. The resultant prolongation of contact between renal tubular cells and ICM amplifies the cytotoxicity of ICM. The osmolarity of the contrast media has also been implicated in the context of CA-AKI – with higher renal toxicity associated with high osmolar agents (4-5x serum osmolarity) vs low osmolar agents (2x serum osmolarity).⁵ AKI in the setting of PVI can be induced by causes other than ICM. Distal embolization of cholesterol crystals caused by manipulation of the atherosclerotic plaque is a potential mechanism of renal injury during PVI. Widespread renal emboli can obstruct renal arterioles, resulting in renal ischemia. In patients with CLI who present with infected ulcers, antibiotics such as beta-lactams or vancomycin have known nephrotoxicity and can contribute or cause AKI.^6,7 

CA-AKI is contemporarily defined as impairment of renal function measured as either a 0.3 mg/dL increase in serum creatinine (SCr) within 48 hours or an increase in SCr >1.5x compared to baseline within 7 days or urine volume <0.5 mL/kg/hr for at least 6 hours in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.⁸ There are various other criteria and definitions of AKI, notably the Acute Kidney Injury Network (AKIN) and the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) criteria. Pertinent to CA-AKI in the setting of PVI, multiple published studies in the literature have consistently defined CA-AKI as an absolute increase of 0.5 mg/dL in SCr.⁹ The prognostic value of these various definitions in comparison with one another has not been definitively validated in the context of PVI.

Prognosis of CA-AKI

In the setting of PCI, CA-AKI is well documented to carry unfavorable prognosis during hospitalization.^10-14 Although the percentage of patients with CA-AKI after PCI who require hemodialysis is low (<1%), these patients have extremely poor prognoses, with in-hospital survival mortality of ~35% and 2-year survival mortality of ~18%.¹⁵ Patients with chronic kidney disease (CKD) who suffer from CA-AKI after PCI have sustained loss of renal function and worsening progression of their kidney disease.¹⁶ These findings suggest that patients who develop CA-AKI following PVI will have similarly poor outcomes. In one study, CA-AKI following PVI was found to be strongly associated with in-hospital adverse outcomes, including death, myocardial infarction, stroke, transfusion, and increased hospital length of stay.¹ 

CA-AKI Incidence and Risk Factors

Grossman et al, using data from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) Vascular Interventions Collaborative registry noted a CA-AKI rate of 3%.¹ Prasad et al found a similar incidence rate (3.5%) in the setting of PVI performed for limb claudication when analyzing data from a different database, the National Inpatient Sample.² Independent risk factors for CA-AKI post PVI are body mass index (BMI) <18 kg/m² or >30 kg/m², diabetes mellitus, heart failure, anemia, CKD, CLI, a requirement for urgent or emergent procedures, and the ratio of contrast volume (CV) to calculated SCr clearance (CCC) >3.¹ The rate of AKI appears to be higher in CLI patients undergoing PVI (10.4%).³

The risk factors for the development of CA-AKI are widespread in patients with PAD (Figure 1). Diabetes mellitus is present in approximately 20%-30% of patients with PAD.¹⁷ The prevalence of heart failure in patients with PAD ranges from 5.3%-13.9%. In a meta-analysis, heart failure prevalence is two-fold higher when compared with the general population without PAD.¹⁸ CKD has a strong association with the development and severity of PAD.¹⁹ Approximately 12%-15% of patients with CKD have PAD,²⁰ and the prevalence of CKD in patients who require PVI due to CLI approaches 29.2%.³ Furthermore, the presence of chronic renal ischemia due to renal artery stenosis may be underappreciated. The prevalence of renal artery stenosis approaches 40% in patients with PAD.²¹ Interestingly, age has not been found to be an independent risk factor, which is consistent with previous studies showing that PVI can be safely performed in elderly patients with low complication rates.^22,23 Analyzing the ICD-9 code for 2003 to 2009 in the National Inpatient Sample, Prasad et al found that the rate of CA-AKI was increasing over time.³ With more PVI being performed on an aging population with a high prevalence of comorbidities, the incidence of CA-AKI will likely continue to increase in the future. 

Review of the Currently Available Methods to Prevent CA-AKI in PVI

Contemporary guidelines from major national and international societies do not provide granular recommendations for CA-AKI prevention. General themes forwarded by position statements and best-practice documents include preprocedural planning. This process includes proper patient selection, AKI risk assessment screening, and management of nephrotoxic medications. These steps remain critical in the prevention of CA-AKI, as no postinjury therapeutic measures have shown benefit. 

Preprocedural preventive strategies. Appropriate patient selection is crucial in the prevention of CA-AKI. As mentioned earlier in this article, extremes of BMI, diabetes mellitus, CKD, heart failure, and a requirement for urgent procedures have been found to be independent predictors for the development of CA-AKI following PVI.¹ In patients with multiple risk factors, physicians should strive to minimize the risk of development of CA-AKI by utilizing preventative techniques or consider alternative therapies for PAD. Multiple risk-assessment tools are available to predict the risk of CA-AKI in the setting of coronary angiography, with the risk score established by Mehran et al the most widely used;²⁴ however, there are no established risk-assessment tools for CA-AKI following PVI. 

Medication management prior to any studies involving ICM is crucial to the prevention of CA-AKI development. Medications such as diuretics, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, sodium glucose co-transporter-2 inhibitors, and antibiotics all have an impact on renal function. The timing of their initiation and chronicity of use should be considered when deciding to administer or hold before PVI. Although not nephrotoxic, metformin should be held before the procedure due to concern for metabolic acidosis. There is evidence that statins might have a role in the prevention of CA-AKI.^25,26 

Periprocedural preventive strategies. During the periprocedural period, volume expansion in most patients is recommended, although these data are largely extrapolated from the coronary literature. Intravenous (IV) fluid administration and hydration are the standard of care in patients undergoing procedures involved ICM. In general, preprocedure oral hydration is recommended.²⁷ The benefits of IV fluid in preventing CA-AKI are well established. Many trials investigating the role of IV fluids in CA-AKI have been done in the setting of coronary procedures, with few data available in the setting of PVI. PVI patients are sometimes included in various trials; however, they often comprise a small percentage of the overall study population. In many cases, the fluid of choice is 0.9% normal saline; however, IV administration of any isotonic fluid appears to be beneficial. There is no superiority of sodium bicarbonate over normal saline, as was demonstrated in the PRESERVE trial.²⁸ Of note, this trial included ~9.5% of non-coronary procedures across all groups. This study also showed that acetylcysteine provided no additional benefits in reducing the rate of CA-AKI.²⁸ The 2011 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines for PCI recommended isotonic crystalloid (1.0-1.5 mL/kg/hr) for 3-12 hours before the procedure, continuing for 6-24 hours post procedure.²⁹ Several other IV hydration protocols have been developed (Table 1).^30-32 

The RenalGuard system (RenalGuard Solutions) represents another novel automated approach to IV fluid hydration. With this system, patients achieve high urine output (>300 mL/hr) by receiving simultaneous isotonic IV fluid and IV furosemide. REMEDIAL II was a randomized, open-label study on patients at high risk of developing CA-AKI, and showed that the use of the RenalGuard system plus oral acetylcysteine was superior to a regimen of isotonic fluid (sodium bicarbonate) plus oral acetylcysteine in patients undergoing coronary angiographies, PCI, and PVI. The study primary endpoint was an absolute increase of ≥0.3 mg/dL from baseline SCr or need for hemodialysis at 48 hours post procedure. REMEDIAL II showed that the use of RenalGuard reduced the primary endpoint event rate by half when compared to the conventional method. Notably, 3 patients in the RenalGuard group and 1 patient in the control group developed pulmonary edema. Of the 294 randomized patients in REMEDIAL II, 24 patients underwent PVI and approximately 21% of all randomized patients had PAD.³³ 

Left ventricular end-diastolic pressure (LVEDP)-guided hydration regimen is also of interest in the realm of CA-AKI prevention. The POSEIDON trial³² showed that LVEDP-guided volume expansion in at-risk patients was superior vs a standard hydration regimen at preventing CA-AKI in patients undergoing PCI. The utility of hemodynamic-guided volume hydration specifically in the setting of PVI is unknown since this population was not included in this trial.³²

Limiting contrast exposure is a central tenant to CA-AKI prevention. The volume of ICM used during the procedure is crucial to the development of CA-AKI. The dose-effect relationship between ICM and CA-AKI has been well documented in the setting of coronary angiography. The median volume of contrast used during PCI was 185 mL (interquartile range, 140-250 mL) according to data obtained from the NCDR Cath-PCI Registry;³⁴ however, the contrast volumes used during PCI varied widely between physicians.³⁵ PVIs typically use less contrast volume, with a reported average volume ranging from 100-160 mL, with wide variations among physicians, clinical situations, and equipment availability.^36,37 The maximum contrast dose that can be safely used during one procedure, or maximum allowable contrast dose (MACD), was first established by Cigarroa et al,³ using the formula: contrast volume (mL) = 5 mL x body weight (kg)/SCr. Besides the MACD, many other thresholds based on CCC have been subsequently developed in the setting of PCI.^38,39 In a review of 58,957 PCIs, patients with a ratio of contrast volume/CCC >2 were associated with increased risk for CA-AKI.³⁹ In the setting of PVI, Grossman et al demonstrated the same dose-effect relationship; patients with a ratio of contrast volume/CCC >3 had higher chances of developing CA-AKI, with an odds ratio of 1.4 (95% confidence interval, 1.1-1.8).¹ The 2016 SCAI expert consensus statement on cardiac cath best practices recommended that the contrast volume administered to the patient should be monitored in real time if possible, and the operator should use the lowest amount of effective contrast volume.⁴⁰ Staged procedures can be planned, or the procedure can be postponed when the maximum dosage of contrast is reached to avoid excessive ICM exposure during a single procedure.

Older ICMs were ionic and hyperosmolar compared with plasma (1400 to 1800 mOsm/kg) and are rarely used today due to their association with an increased risk of CA-AKI and adverse side effects.⁵ Low-osmolar and iso-osmolar contrast agents were developed later and resulted in lower rates of CA-AKI compared with older ionic and hyperosmolar contrast agents. Iodixanol (Visipaque; GE Healthcare) is the only available iso-osmolar contrast media in the United States. Iodixanol is non-ionic and has an osmolarity of 290 mOsm/kg. Non-ionic low-osmolar agents (osmolarity ranging from 500-850 mOsm/kg) included iohexol, ioversol, and iopamidol. Regarding their nephrotoxicity and CA-AKI, there remains debate regarding the superiority between iso-osmolar and low-osmolar contrast media.^41,42 However, low-osmolar contrast media were reported to cause more limb discomfort during injection when compared with iso-osmolar agents in patients undergoing peripheral angiography. There are randomized, controlled, multicenter trials that found iso-osmolar agents causing less pain during injections and providing similar diagnostic accuracy when compared with low-osmolar agents.^43,44

Contrast modulation devices, controlled injector systems, and carbon-dioxide (CO₂)-based angiography have all been used to reduce ICM exposure. Postprocedure monitoring for the development of CA-AKI and avoiding serial administration of ICM without time for renal recovery are also recommended practices.

Dilution of contrast is one of the simplest methods to prevent CA-AKI, specifically in the setting of PVI. By diluting contrast with normal saline (NS; usually with 1:2 or 1:3 ratios of ICM:NS), the operator can significantly reduce the patient’s iodine exposure. With the advent of advanced digital subtraction angiography (DSA), the image quality is often preserved; however, quality can be affected in certain cases, especially in large vessels, as was demonstrated in Jens et al.³⁷ Their study investigated the use of contrast dilution in PVI, but was limited by a small sample size (n = 60). Conversely, if image quality is poor, then dilution of contrast can lead to multiple injections and theoretically increase the total volume of contrast used during the procedure.³⁷ Further study is needed to investigate the effectiveness of contrast dilution in the prevention of CA-AKI. 

CO2 is an inexpensive, highly soluble, non-allergic, non-nephrotoxic contrast agent that could be used in peripheral procedures (Figure 2).⁴⁵ Compared with ICM, PVI using CO2 has a lower incidence of CA-AKI.⁴⁶ These qualities make CO2 an attractive option to replace ICM when there is a concern for CA-AKI or contrast allergy. When injected into the bloodstream, CO2 displaces blood and then dissolves rapidly into the bloodstream to be eliminated by the lung. When used during angiography, the displacement of blood by CO2 renders the image of the desired vessels. CO2 is safe to use in patients with chronic lung disease if they can compensate with hyperventilation. 

However, CO2 angiography is not without its limitations. Due to the risk of neurotoxicity, CO2 angiography should only be used for infradiaphragmatic angiography (although this issue is largely avoided in the realm of lower-extremity PVI).⁴⁷ Because CO2 is odorless and colorless, contamination with room air (resulting in an air embolism) can occur. Due to the buoyancy of CO2, the gas does not uniformly displace blood but tends to rise to the anterior, non-dependent portal of the vessel. This issue is particularly prominent when CO2 is injected in large vessels or when insufficient CO2 is injected, resulting in poor image quality. On the other hand, when an excessive volume of CO2 is injected, not only can the operator overestimate the dimension of the vessel, a bolus of CO2 may be retained in the vessel, a process known as “trapping.” This phenomenon can also potentially cause ischemia. For this reason, a direct connection from the source of CO2 to the catheter is avoided. 

CO2 angiography is also limited by poor accessibility. Experience is required to obtain adequate image quality and to avoid the potential complications mentioned above. Usage of CO2 angiography generally involves a CO2 tank and a 3-way stopcock in tandem with tubing. A dedicated CO2 injector was unavailable in the United States for many years. A newly developed delivery system for CO2, such as the CO₂mmander system (AngioAdvancement) might have utility in streamlining the procedure. The CO2mmander system is disposable, compact, and portable, which eliminates the needs for cumbersome assembly. Furthermore, it is a closed system that reduces risks for contamination by room air. 

A contrast-delivery modulation system, such as the Dyevert Plus (Osprey Medical), has been shown to reduce ICM delivery during coronary and peripheral angiography. These systems rely on a pressure-compensating valve to maintain a constant and appropriate injection pressure to minimize excessive contrast delivery while maintaining image quality. The Dyevert Plus system also offers real-time monitoring of actual contrast volume delivered to the patient. This real-time monitoring allows the operator to gauge the total ICM used and therefore potentially administer reduced dosages. The utility of this device was studied in both coronary angiography and peripheral interventions.^48,49 Small, randomized trials have shown significantly less contrast volume (~40% reduction) used during PVI while utilizing these systems.^49,50 However, whether this dose reduction translates to a reduction in the rate of CA-AKI remains unproven.

Automated contrast injecting systems, such as the ACIST injection system (ACIST Medical Systems) remove the need for manual contrast injection. Instead, a handheld controller is used, and the process of contrast injection is simplified with a press of a button. This system allows the operator to control and monitor various parameters during the procedure, such as contrast volumes used during each injection, the total volume of contrast used, contrast flow rate, and pressure. This system provides a measurement of total contrast volume used during the case. Retrospective studies of coronary angiography have shown that using an automated injector reduces the volume of ICM when compared with manual contrast injection.^51,52 A meta-analysis reviewing the use of this tool during coronary angiography and PCI showed that automated injectors reduced overall contrast volume by 45 mL during each procedure and reduced the incidence of CA-AKI by 15%.⁵³ The lack of availability of automated contrast injectors in many catheterization labs remains a challenge. This tool also has not been studied extensively in the setting of PVI.

Intravascular imaging offers alternatives and adjunctive modalities to x-ray and ICM-based imaging, which could aid in the prevention of CA-AKI when less volume of ICM is used. In contrast to two-dimensional x-ray based angiography, intravascular imaging allows physicians to visualize the diseased vessel internally as opposed to externally. Several options are available, including optical coherence tomography (OCT) and intravascular ultrasound (IVUS). IVUS images are generated using high-frequency sound waves to penetrate tissues. The reflections of the sound wave off vascular structures are computerized to produce a multidimensional image. Using IVUS, PCI without ICM (zero-contrast PCI) has been performed and was found to be safe in experienced centers.⁵⁴ The utilization of a similar approach in PVI remained to be studied. OCT involves near-infrared light for intravascular visualization and has been studied in the setting of coronary procedures (Figure 3).⁵⁵ OCT typically provides higher image resolution compared with IVUS, which better aids the characterization of the lesion and avoids injury to intimal tissues during manipulation. Utilizing OCT, devices such as the Ocelot and Pantheris catheter (Avinger) have emerged to aid lesion crossing and atherectomy during PVI. The use of OCT requires the displacement of red blood cells from the imaging field before the acquisition of imaging. For this purpose, ICM is widely used as a flushing agent. Overall, the use of intravascular imaging is underutilized and understudied in the context of PVI, but may help reduce the need for angiography.

Conclusion

CA-AKI is a severe complication from PVI and is associated with poor outcomes and increased mortality. The incidence of CA-AKI appears to be increasing over the past decade. Many strategies to prevent CA-AKI in the setting of PVI are extrapolated from coronary studies. Identification of at-risk patients remains the cornerstone of CA-AKI prevention. Proper volume expansion and limitation of ICM volume during the procedure is strongly recommended. Several alternatives and modalities, each with its unique advantages and disadvantages, are available to aid physicians in limiting the amount of contrast used. Further work on PVI-specific risk prediction tools and prevention strategies is warranted.

From ¹the Department of Medicine, Division of Cardiology, ²Department of Medicine, Division of Nephrology, UT Health San Antonio, San Antonio, Texas. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

The authors report that patient consent was provided for publication of the images used herein.

Manuscript submitted March 1, 2020, final version accepted March 9, 2020.

Address for correspondence: Anand Prasad, MD, FACC, FSCAI, RPVI, Interventional Cardiology and Vascular Medicine, Department of Medicine, Division of Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7872, San Antonio, TX 78229-3900. Email: anandprasadmd@gmail.com