Acute kidney injury (AKI) is a frequent occurrence in hospitalized patients and its overall incidence appears to be increasing. In addition, the number of patients in whom AKI is preceded by exposure to iodinated contrast is also increasing (see Figure 1). Patients who develop AKI in hospital are typically those undergoing major surgical procedures and individuals suffering from hemodynamic insults, such as gastrointestinal bleeding, myocardial infarction, or sepsis. AKI also occurs in outpatients, where the etiology is more likely to be caused by nephrotoxins such as contrast media administered during coronary angiography and contrast-enhanced CT exams. For both inpatients and outpatients with AKI, regardless of etiology, there is a strong association between the occurrence of AKI and adverse events.1 These adverse events include increased length of hospital stay, greater hospital costs and in-hospital mortality, increased cardiovascular events, progression to end-stage kidney disease, and increased mortality at one year.
The association between AKI and adverse outcomes has been found across diverse cohorts of patients and etiologies of AKI.1 Despite this consistent association, it remains unclear whether the kidney injury itself is the cause of the subsequent adverse events. This is particularly relevant when discussing the relationship between AKI and events that occur months to years after the episode that produced the AKI. It could be argued that there is something about the patients who develop AKI that predisposes them to these long-term adverse events. For example, patients who have a significant burden of cardiovascular risk factors (e.g. those with diabetes and hypertension) are more likely to suffer AKI following a hemodynamic insult and independently to have a higher risk for long-term cardiovascular events such as stroke or myocardial infarction, and even death. In such patients, AKI may be a ‘marker’ of cardiovascular risk factor burden. Alternatively, AKI may in some direct way accelerate the atherosclerotic process, increasing the likelihood of a future stroke, acute myocardial infarction, or death. In these patients, AKI may be a cause of the later adverse events. Distinguishing between these two possibilities is not easy. However, the impact of these two possible explanations is vastly different.
Randomized Trials and What They Can Tell Us About the Link Between Acute Kidney Injury and Long-term Adverse Events
One approach to distinguishing between these possible explanations for the association between AKI and adverse event rates is to look at data from prospective randomized trials in which the goal of the trial was to prevent AKI. In such trials, two or more different therapeutic approaches to prevention of AKI are usually compared (active versus placebo, comparator one versus comparator two, etc.). A large randomized trial is expected to distribute the baseline risk factors for later cardiovascular events equally among the treatments being compared. If the baseline risk factor burden is the primary determinant of late cardiovascular adverse events and AKI is just a ‘marker’ of baseline risk factor burden, both arms should have an equal number of cardiovascular events. If, on the other hand, AKI causes the late cardiovascular events, if one arm is superior to the others in preventing AKI it would also be expected to reduce the incidence of late adverse events (see Figure 2).
The CARE Trial
The Cardiac Angiography in Renally Impaired Patients (CARE) trial was a prospective, randomized, double-blind trial that compared two iodinated contrast agents (iopamidol and iodixanol) for the prevention of AKI in patients with moderate to severe chronic kidney disease who underwent coronary angiography.2 Four hundred and fourteen patients with an estimated glomerular filtration rate <60ml/minute were enrolled at 25 sites in North America. The average age was 71 years and >40% of the patients also had diabetes; these patients were considered to be the group most at risk for developing AKI following the administration of iodinated contrast media. The CARE trial defined AKI (CIN) as a rise in serum creatinine of ≥0.5mg/dl or ≥25% within five days of exposure to contrast media. On average, the post-contrast serum creatinine determinations were made 69 hours after exposure to contrast. When the trial was completed in 2007, the results indicated that the incidence of AKI (CIN) was statistically similar with both contrast agents.
The patients in the original trial were re-contacted after one year with the goal of assessing long-term adverse event rates (CARE follow-up trial).3 Only 294 of the original 414 agreed to follow-up data collection. These 294 were not different in any baseline cardiovascular risk factors from the 120 who did not participate.
In the original trial, there was no statistical difference between the two contrast agents in the incidence of AKI (CIN), although a trend in favor of iopamidol was seen. Of the 414 patients in the original trial, 350 had simultaneous measurements of cystatin C with the serum creatinine measurements. The cystatin C measurements suggested that there were real differences between the two contrast agents in the incidence of AKI (see Table 1).
Cystatin C is a small molecular protein produced by all nucleated cells of the body. It is produced at a constant rate and eliminated from the body by glomerular filtration. A meta-analysis of many studies have reported that changes in cystatin C are more sensitive and specific for AKI than are serum creatinine changes.4 Furthermore, cystatin C distributes in extracellular volume, while creatinine distributes in total body water. As a result of the smaller volume of distribution, retention of cystatin C following a reduction in glomerular filtration rate results in a faster rise in cystatin C compared with creatinine.5
The finding that there was a significant difference in the incidence of AKI (CIN) between the two contrast agents based on serum cystatin C measurements meant that assessment of the long-term adverse event rates might provide a clue as to whether AKI was the cause of those events. If there was no difference in event rates despite the difference in the incidence of AKI, it would imply that the baseline cardiovascular risk factors had been equally distributed by the randomization process and that they were determinants of late adverse events. On the other hand, if the differences in the incidence of AKI were paralleled by differences in long-term outcomes, it would imply that AKI had a causal relationship with those outcomes.
In the CARE follow-up study, three cystatin C definitions (≥15, ≥20, and ≥25%) and one serum creatinine definition definition (≥0.3mg/dl increase) were studied.3,6 As in the original CARE study, these measurements were made from blood samples acquired two to three days after exposure to contrast media. Use of these four definitions resulted in a two- to four-fold higher incidence of AKI (CIN) than that found in the original CARE trial based on the traditional definitions. Additionally, each of these more sensitive definitions was associated with a statistically significant two- to three-fold increase in late adverse events, including acute myocardial infarction, stroke, end-stage kidney disease, and death. Thus, these definitions are valid predictors of adverse events and, as such, are clinically meaningful.
Using these new definitions of AKI (CIN), patients who developed AKI had a two- to three-fold increase in the incidence of adverse events at one year of follow-up.3 When patients who received the contrast agent that produced the least amount of AKI (iopamidol) were compared with those receiving the comparator contrast agent (iodixanol), there was a statistically significant reduction in long-term adverse events. This was the case even after adjustments for a number of cardiovascular risk factors, including age, gender, presence of diabetes, hypertension, congestive heart failure, severity of coronary artery disease, baseline level of kidney function, and left ventricular ejection fraction. The parallel reduction in the incidence of AKI and long-term adverse event rates supports the hypothesis that AKI causes the long-term adverse events (see Figure 2).
In the original CARE trial, two contrast agents were compared. Each agent was eliminated from the body via renal excretion with a half-life of a few hours. Therefore, it is very unlikely that either agent could influence cardiovascular events occurring in the distant future. Only through the ability of one contrast agent to reduce the incidence of AKI (CIN) is there a biologically plausible mechanism for affecting long-term adverse events.
How Acute Kidney Injury Causes Long-term Adverse Events
One of the obstacles to acceptance of the concept that AKI causes long-term adverse events has been the lack of a clear mechanism for such an association. Further undermining our ability to embrace a pathogenic link between AKI and long-term adverse outcomes has been the observation that ‘acute’ often translates to temporary, reversible, and mild. However, evidence suggests that this is rarely the case.
AKI is currently defined using a marker of glomerular filtration rate such as creatinine or cystatin C. These markers tell us about kidney function rather than kidney injury itself. These markers are not particularly sensitive to small changes in kidney function, particularly when kidney function is normal or only mildly abnormal prior to the insult. Furthermore, the kidney has adaptive mechanisms to maintain glomerular filtration rate (function) even in the absence of intact nephrons (structure).
As an example, when a donor gives a kidney to a recipient for transplantation, the glomerular filtration rate falls only slightly despite the loss of 50% of the nephron mass. The remaining nephrons in the donor are capable of increasing their individual filtration rates, so-called hyperfiltration, mitigating the fall in glomerular filtration rate to less than the expected 50%.
The same phenomenon of compensatory hyperfiltration occurs following AKI. While some nephrons that are not irreversibly damaged will recover, others are lost forever. However, measurement of glomerular filtration rate and therefore its surrogates, serum creatinine and cystatin C, will not reveal this nephron loss unless the loss of function is so great that it cannot be compensated by the remaining nephrons. Properly understood, the return of serum creatinine to near baseline following AKI is not an assurance that either the number of nephrons or individual nephron function has returned to baseline levels.
This hyperfiltration response is particularly relevant to late adverse events. First, hyperfiltration occurs as a result of an increase in blood pressure within the glomerular capillary. Over time, this glomerular hypertension damages the capillaries of the glomerulus, resulting in fibrosis and further loss of filtration surface area. Ultimately, a nephron unit becomes non-functional and the need for further hyperfiltration in the remaining nephrons escalates. A vicious cycle is started in which nephron loss begets nephron loss.7 As nephrons are lost and global glomerular filtration gradually declines, a variety of substances accumulate in the blood that affect the natural history of atherosclerosis, accelerating damage to vessels in general. These non-traditional risk factors for cardiovascular disease are still being defined and are beyond discussion here. Suffice to say that chronic kidney disease (chronic loss of glomerular filtration capacity) is one of the strongest risk factors for cardiovascular events.8
Acute Kidney Injury Causes Chronic Kidney Disease
The premise that some AKI results in chronic kidney disease is supported by a great deal of observational data. Some of these data are derived from large administrative databases that compare hospital International Statistical Classification of Diseases (ICD)-9 codes on discharge with the Centers for Medicare (CMS)–US Renal Data System (USRDS), which tracks nearly all patients who enter into dialysis care. For example, patients who had an episode of AKI requiring in-hospital dialysis were 28 times more likely to progress to stage IV or V chronic kidney disease over an eight-year follow-up period compared with patients with similar baseline kidney function who did not sustain AKI while hospitalized.9
Similar observations have been made from other administrative databases associating AKI with the development of end-stage kidney disease.10,11 Smaller, single-center studies have been able to follow kidney function in patients who sustained AKI while in hospital and report more rapid loss of kidney function over time than those without AKI. For many, but not all, of these studies, the index episode of AKI was quite severe, requiring in-hospital dialysis support.
For patients who undergo cardiac angiography, the incidence of AKI ranges from 1–2% in the absence of any risk factors to >50% in the setting of baseline renal insufficiency, diabetes, and hemodynamic instability.12 The need for dialysis support is incredibly infrequent in these individuals. Nevertheless, there is evidence that patients who sustain even mild AKI (CIN) lose kidney function at a faster rate following the injury.13 Prevention of AKI (CIN) by pharmacological prophylaxis with antioxidant therapy reduces the rate of loss of kidney function in small single-center studies.13,14
The CARE follow-up trial adds to a growing body of literature relating AKI to long-term adverse events. In the CARE trial, the subjects were predominately outpatients and the episode of AKI (CIN) was relatively mild and did not require dialysis treatment. The patients were studied prospectively, and exhaustive baseline data regarding cardiovascular risk factors were collected. AKI (CIN) was associated with a doubling of cardiovascular event rates assessed at approximately one year. When AKI was minimized, the long-term adverse event rates were also reduced for each of the composite end-points. Even after adjusting for baseline cardiovascular risk factors, there remained a significant reduction in one-year event rates, supporting the hypothesis that AKI (CIN) caused the adverse events. The CARE follow-up study did not include changes in long-term kidney function. Therefore, we could not assess whether kidney function worsened in those who experienced AKI. A model of the interaction between baseline cardiovascular risk factors and AKI is shown in Figure 3.
The data from the CARE follow-up trial suggesting a causal relationship between AKI and long-term adverse events are a call to action. First and foremost, regardless of the strategies used, all trials for the prevention of AKI should collect data on long-term adverse outcomes. Only through the collection of such data can the causal association be critically evaluated. Will all therapies that reduce the incidence of AKI result in reductions in long-term adverse outcomes? Are there some populations at increased (or decreased) risk for long-term adverse outcomes after the development of AKI (CIN)? Answers to these questions might tell us something more about the pathogenic mechanisms underlying this causal link.
Second, we need to develop and validate biomarkers of kidney injury rather than function. Relying on functional markers masks real nephron loss and/or damage. We have little information about how long it takes for the kidney parenchyma to complete the process of recovery from acute injury. We only have knowledge of the trajectory of serum creatinine. Is it possible that serum creatinine can return to ‘baseline levels’ while evidence of ongoing injury and inflammation is still present?
The impact of AKI on long-term adverse events is not trivial. Patients who develop and recover from AKI should undergo more intense surveillance for progressive loss of kidney function. Treatments to reduce kidney function loss though management of hypertension, proteinuria, hyperglycemia, and perhaps hyperlipidemia should be intensified in this group. Although there are sparse evidence-based guidelines for these patients, efforts to treat known cardiovascular risk factors should also be heightened in these patients. Finally, more research regarding the role and manipulation of non-traditional risk factors is needed. CARE and CARE follow-up represent another step in shifting our understanding of the relationship between AKI and longterm adverse events. It is clearly important that these observations be re-tested in future trials.