Definitions, Terminology & Clinical course

Post-Contrast-AKI: Terminology and definitions

Because of the recent developments there is confusion about terminology. Terms as post-contrast acute kidney injury, contrast-associated acute kidney injury, and contrast-induced acute kidney injury or contrast-induced nephropathy are incorrectly used interchangeably.

Therefore, the working group suggests adaptation of the suggestion of the American College of Radiology (ACR) Committee on Drugs and Contrast Media, put forward in their Manual on Contrast Media for more uniformity (ACR Manual, 2017).

Post Contrast Acute Kidney Injury (PC-AKI) is a general term used to describe a sudden deterioration in renal function that occurs within 48 hours following the intravascular administration of iodine-containing contrast medium. PC-AKI may occur regardless of whether the contrast medium was the cause of the deterioration. PC-AKI is a correlative diagnosis.

Contrast-Induced Acute Kidney Injury (CI-AKI) or Contrast-Induced Nephropathy (CIN) is a specific term used to describe a sudden deterioration in kidney function that is caused by the intravascular administration of iodine-containing contrast medium; therefore, CI-AKI/CIN is a subgroup of PC-AKI. CI-AKI/CIN is a causative diagnosis.

The ACR acknowledges that very few published studies have a suitable control group to permit the differentiation of CI-AKI/CIN from PC-AKI. Therefore, the incidence of PC-AKI reported in clinical studies and the incidence of PC-AKI observed in clinical practice likely includes a combination of CI-AKI/CIN (i.e., AKI caused by contrast medium administration) and AKI unrelated to contrast medium administration (i.e., AKI coincident to, but not caused by contrast medium administration). It should be clear that these terms are not interchangeable.

PC-AKI is not synonymous with CI-AKI / CIN (ACR Manual, 2017).

Definitions and their history

In critical care, acute renal failure is a complex disorder with a wide variety of aetiologies and possible risk factors. Despite improved knowledge from animal studies, there was a lack of uniform definition of this disorder. This challenge has been taken on by multiple groups in the Nephrology community, among them the Acute Dialysis Quality Initiative (ADQI) (Bellomo, 2004) and the Kidney Disease: Improving Global Outcome (KDIGO) (Levey, 2005) groups.

During the first meeting of the Acute Kidney Injury Network (AKIN), a network of experts in Critical Care and Nephrology, the term Acute Kidney Injury (AKI) was suggested as the preferred uniform terminology for acute renal failure. This was diagnosed as “an abrupt (within 48 hours) reduction in kidney function currently defined as an absolute increase in serum creatinine (sCr) of ≥ 0.3 mg/dl (≥ 26.4 μmol/l), a percentage increase in serum creatinine of more than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 ml/kg per hour for more than six hours)” (Mehta, 2007). In clinical practice a 50% increase in sCr >3 and <7 days can be used. This definition is thus applicable to all forms of AKI and is not specific for contrast-induced AKI. This was subsequently adapted into the KDIGO Practice Guidelines in 2012. According to this guideline, AKI can be subdivided in 3 stages (see Table 1) according to criteria adapted from the RIFLE (Risk, Injury, Failure, Loss, End Stage) criteria (Drüeke, 2012):

Table 1: KDIGO staging of AKI

*Stage*	*Serum creatinine criteria*	*Urine output criteria*
1	sCr increase ≥0.3 mg/dl (≥26.5 μmol/l), or sCr increase ≥1.5 to 1.9x baseline	<0.5 ml/kg/h for 6 to 12h
2	sCr increase >2.0 to 2.9x baseline	<0.5 ml/kg/h for ≥12h
3	sCr ≥4.0 mg/dl (≥354 μmol/l) sCr increase >3.0 x baseline or initiation of renal replacement therapy	<0.3 ml/kg/h for ≥24h Anuria for ≥12h

Of note 1 mg/dl serum Creatinine equals 88,4 µmol/l.

In the mid 1990s, the Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) was founded, a group of experienced CM researchers from Radiology, that was set out to make expert-based guidelines. The most frequently used definition of Contrast-Induced Nephropathy (CIN), is from their first renal guideline: “CIN refers to a condition in which an impairment in renal function (an increase in serum creatinine by more than 25% or 44 µmol/l (or 0.5 mg/dl) occurs within 3 days following the intravascular administration of a contrast medium in the absence of an alternative aetiology” (Morcos, 1999). More stringent definitions have been used in older studies, e.g. using a sCr increase >1 mg/dl [88 µmol/l] or 50% (Aspelin, 2003). However, these have not really been used widely in recent times.

This resulted in another confusion that has still not been adequately resolved by a consensus definition (Endre, 2010; Meinel, 2014). It has been shown in multiple studies that the percentage of patients with CIN is largely dependent on the definition used (Jabara, 2009; Pyxaras, 2015; Weisbord, 2008).

A relative increase in sCr of >25% has been the most sensitive indicator, whereas absolute value definitions led to lower rates of CIN. In some studies relative increases in sCr were found to overestimate CIN and absolute values were preferable (Budano, 2011), while in other studies relative definitions were stronger associated with prognostic relevance in coronary angiography (Pyxaras, 2015). A recent study showed that the combination of an absolute sCr increase >0.3 mg/dl [25 mol/l] or a relative sCr increase >50% might be the most optimal definition (Parsh, 2016).

However, these figures of CIN are usually not well related to hard clinical endpoints such as (short-term) renal replacement therapy dependency, morbidity or mortality. Some studies in critically ill populations have shown a benefit of the AKIN-definition of post-contrast AKI on ICU mortality (Lakhal, 2011).

Already in 2006, a CIN Consensus Working Panel formed by GE Healthcare with experts from various disciplines indicated that the ADQI-RIFLE criteria may be important in the future for defining PC-AKI (McCullough, 2006). Many researchers in radiology and cardiology are now moving towards adaptation of the AKIN criteria as the standard for studies on contrast-induced AKI (Garfinkle, 2015). Therefore, we suggest, similar to the European Renal Best Practice (ERBP) working group in their comment on the KDIGO 2012 practice guidelines on AKI, that there seems to be no good reason why the definition of PC-AKI (or CI-AKI) should be different from the general definition of other forms of AKI (Fliser, 2012; Kooiman, 2016; Thomas, 2015), even though CI-AKI /CIN and PC-AKI are not completely interchangeable.

Clinical Course and Incidence

PC-AKI is an iatrogenic renal injury that follows intravascular administration of CM in susceptible individuals. (Rear, 2016). The proliferation in imaging methods and interventions involving administration of intravascular CM has significantly increased the number of patients exposed to CM and consequently the number of patients at risk for PC-AKI.

Discrimination between different causes of AKI in patients subjected to iodine-containing CM administration is difficult. In most of cases PC-AKI is mild and reversible with returning of renal function to baseline or near baseline values within 1-3 weeks (Mehran, 2006; Guitterez, 2002). As common for all forms of AKI, the occurrence of PC-AKI has shown to be a marker for increased short- and long-term morbidity and/or mortality and prolonged hospital stay (Gupta; 2005; Gruberg, 2000; Mitchell, 2015; Kooiman, 2015; Rihal, 2002; Rudnick, 2008).

Various studies suggest that the route of administration of iodine-containing CM (intra-arterial versus intravenous) and the type of procedure (i.e. catheter-based angiography versus CT imaging) can have a substantial impact on the incidence of PC-AKI. (Dong, 2012) However, in four retrospective studies the risk of PC-AKI and clinical course did not differ in patients who underwent both intra-arterial and intravenous contrast administration within a restricted time span. (Karlsberg, 2011; Kooiman, 2013; Tong, 2016; McDonald, 2016)

The cause of AKI following catheter angiography is in many instances multifactorial and may erroneously be diagnosed as PC-AKI. (Keeley, 1998) For instance, catheter-based procedures as compared to contrast-enhanced computed tomography (CE-CT) may be complicated by haemodynamic instability leading to post-interventional AKI, which may be misinterpreted as contrast-induced nephropathy (Bruce, 2009; Newhouse, 2008). In addition, cholesterol emboli, aortic plaque fragments and thrombi may be physically dislodged during catheter manipulation, leading to micro-embolization of the kidney and post-procedural impairment of kidney function (Wichmann, 2015).

Two recent meta-analyses of 40 and 42 studies in about 19,000 patients undergoing CE-CT revealed a weighted pooled incidence of PC-AKI of 6.4% (95%CI 5.0-8.1%) and 5.0% (95%CI 3.8-6.5%). (Kooiman, 2012; Moos, 2013) In the meta-analysis of Moos et al. chronic kidney disease (CKD), diabetes, malignancy, age >65 years and use of non-steroidal anti-inflammatory drugs (NSAID’s) and in the meta-analysis of Kooiman et al. CKD and diabetes were associated with an increased risk. In about 1% of all patients (follow-up one week to two months after CE-CT) the renal function decline persisted, but the weighted pooled incidence of renal replacement therapy was as low as 0.06%. (Kooiman, 2012) The authors of this meta-analysis conclude that, given the low incidence of PC-AKI in general and the rare occurrence of a persistent decline in renal function, CM in the setting of a CT can be safely administered to the vast majority of patients. However, as emphasized by the authors, since in most of the studies pre- and post-hydration was performed in patients at high risk for PC-AKI, the results are not generalizable to high risk patients without pre- and/or post-hydration.

Meta-analyses of non-randomized studies comparing outcomes of patients who underwent CT with and without iodine-containing CM bear the risk of selection bias. Recently, propensity score matching has been introduced to the field of PC-AKI. Propensity score matching is a statistical method used in observational studies with low incidence of outcome under study that takes measured confounding into account (Rosenbaum, 1984). McDonald JS, et al. performed a propensity score-based matched study in over 12,500 patients, and did not find an increased risk of PC-AKI, acute dialysis, or 30-day mortality in patients who underwent CE-CT versus those who did not. (McDonald, 2014) Using propensity-score based matching in over 17,500 patients Davenport et al. also did not observe an increased risk for AKI in patients with normal renal function after intravenous CM administration for CT, but they reported an increased incidence of AKI in patients with an eGFR <30 ml/min/1.73m² (Davenport, 2013). These findings suggest that the incidence of CI-AKI in patients undergoing contrast-enhanced CT with intravenous iodine-containing CM administration is likely to be substantially lower than previously estimated. However, the clinical course of AKI after CE-CT may not always be so favourable as evidenced by the abovementioned studies. In a prospective observational study concerning 633 emergency department patients undergoing CE-CT without pre-hydration PC-AKI occurred in 70 patients (11%), with persistent renal failure at one-year follow-up in 11 of these patients. (Mitchell, 2015) It should be emphasized that these patients had an emergent indication for CE-CT and might therefore have other risk factors (such as haemodynamic instability) for AKI.

In 5244 patients with ST-Elevation Myocardial Infarction (STEMI) treated with PCI the incidence of PC-AKI for patients with a baseline eGFR of >90, 60-90, 30-59 and <30 ml/min/1.73 m² was 2.1%, 3.4%, 7.3% and 1.8%, respectively, underlining pre-existent CKD as a risk factor of PC-AKI. (Vavalle, 2016) The relatively low incidence of PC-AKI in the group of patients with an eGFR <30 ml/min/1.73 m² may be related to the small number of patients (n=89) present in this subgroup. Impaired renal function at presentation and development of PC-AKI were highly associated with worse clinical outcome, including death. A meta-analysis of 39 observational studies including 139,603 participants that investigated cardiovascular outcomes in those with PC-AKI demonstrated an increased risk of mortality, cardiovascular events, renal failure and prolonged hospitalization. (James, 2013) Baseline characteristics that simultaneously predispose to both mortality and PC-AKI were regarded as confounders. The reported incidence of end stage renal disease ranged from 0% to 0.2% in those without PC-AKI and from 0.2% to 4.5% in those with PC-AKI. In a more recent study consisting of 92,317 PCI procedures performed in 90,383 patients the incidence of PC-AKI was 2.3% and of renal replacement therapy 0.3%. (Kooiman, 2015) As expected patients developing PC-AKI had a greater burden of co-morbidity at baseline and were more likely to have adverse in-hospital outcomes. Using propensity-score based matching (1,371 patients with PC-AKI versus 5,484 patients without PC-AKI) in-hospital major adverse clinical outcomes (in-hospital mortality, cardiogenic shock, heart failure, stroke, bleeding and new requirement for dialysis post-PCI were considerably and significantly higher in AKI versus non-AKI patients and nearly one-third of the in-hospital mortality risk post PCI appeared to be attributable to AKI, demonstrating its clinical importance. (Kooiman, 2015)

In conclusion, the incidence of PC-AKI after intravenous or intra-arterial iodine-containing CM administration in general is low and directly related to the presence and severity of CKD prior to contrast administration and concomitant co-morbidities as demonstrated by propensity-score based matching analyses. The decline in renal function is mostly transient, but in rare instances renal replacement therapy is required with reported incidences of 0.06% after CE-CT and 0.2% to 0.6% post PCI. PC-AKI is a marker of poor outcomes, including increased short- and long-term mortality. Whether there is a causal relation between PC-AKI and poor outcomes remains unclear. However, reducing the incidence of PC-AKI in high risk patients (such as those undergoing emergent PCI, or with an eGFR <30 ml/min/1.73m²) by optimal risk stratification and preventive measures, remains a major goal in clinical practice.

Terminology of the routes of CM administration

A difference has been made in guidelines between intravenous and intra-arterial CM administration. Intravenous CM administration implies that the CM will reach the renal arteries after dilution by circulation through the right heart and pulmonary or a systemic vascular bed. The same applies to intra-arterial CM administration with second pass renal exposure administrations, that is: administration distal to the renal arteries and to CM administration after selective catheterisation of the suprarenal aortic side branches, e.g. injections via catheters in the carotid, subclavian, brachial, coronary and mesenteric arteries, except for the minimal back flow into the aorta of which only 20% will reach the renal arteries directly. In intra-arterial CM administration with first pass renal exposure the CM will reach the renal arteries without being diluted by a capillary bed, as is the case when the CM is injected via catheters in the left ventricle, thoracic aorta, suprarenal abdominal aorta, or selectively in the renal arteries.

Since this guideline only uses a single cut-off value of eGFR <30 ml/min/1.73m² for preventive IV hydration, the distinction between IV or IA iodinated CM is largely theoretical and has no prevention consequences. Therefore, both IV and IA iodinated CM administration will be referred to by the general term “intravascular CM administration”.

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