NATIONAL HARBOR, MD—The prevalence of acute kidney injury (AKI) is on the rise, with its attendant dangers for short- and long-term health. While preventable risk factors for AKI have been identified, practice patterns to stem the condition's rise are inconsistently applied.
This state of affairs led to the development of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury, available at www.kdigo.org. This first evidence-based clinical practice guideline for AKI also was a hot topic at the National Kidney Foundation (NKF) 2012 Spring Clinical Meetings, where a sneak peek of the soon-to-be-released NKF Kidney Disease Outcomes Quality Initiative (KDOQI) commentary on the guideline was presented.
“There is enormous variation in how the condition is managed across the planet, and therefore there's a need for standardization,” said John Kellum, MD, Cochair of the work group behind the KDIGO guideline and Professor of Critical Care Medicine at the University of Pittsburgh. “That was the reason for choosing AKI. We were trying to standardize the way that this disorder is identified, categorized, and managed.”
Norbert Lameire, MD, PhD, of Ghent University Hospital in Ghent, Belgium, chaired the work group with Dr. Kellum.
Definition and Staging
One of the most discussed topics covered in the extensive document appears right at the beginning: the need for a clear definition and staged classification of acute kidney injury (Recommendations 2.1.1, 2.1.2, and 2.1.3).
In the guideline, AKI is defined by the presence of any one of the following three indicators: a serum creatinine increase of 0.3 mg/dL or higher within 48 hours; a rise in serum creatinine to 1.5 times baseline or greater, which is known or presumed to have occurred within the prior seven days; or urine volume less than 0.5 mL/kg/h for six hours.
“I think it is important to have a definition, and there has been a lot of debate about what the appropriate definition is,” said Ajay K. Singh, MBBS, MBA, Director of Global Programs and Associate Professor of Medicine at Harvard Medical School, a physician in the Division of Renal Medicine and the Director of Postgraduate Medical Education in the Department of Medicine at Brigham and Women's Hospital, and Chair of the Nephrology Times Editorial Board.
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“I think this is a good start. I don't believe that this definition of AKI is a definition that necessarily most clinicians will adopt because it is complicated and not as straightforward as many have hoped for. It's better to have a definition as opposed to no definition, but I don't think this is the one most clinicians will functionally use.”
As the risk for death and dependence on renal replacement therapy rises with higher AKI stage, and since accumulating evidence suggests that even after the apparent resolution of acute kidney injury, risks of cardiovascular disease, chronic kidney disease, and mortality linger, the work group recommended a stage-based approach to AKI evaluation and management that includes parameters for serum creatinine and urine output:
* Stage 1, serum creatinine 1.5–1.9 times baseline or an increase of at least 0.3 mg/dL, or urine output less than 0.5 mL/kg/h for six to 12 hours.
* Stage 2, serum creatinine 2.0–2.9 times baseline, or urine output less than 0.5 mL/kg/h for at least 12 hours.
* Stage 3, serum creatinine 3.0 times baseline, an increase in serum creatinine to 4.0 mg/dL or higher, initiation of renal replacement therapy, or a decrease in estimated glomerular filtration rate (GFR) to less than 35 mL/min/1.73 m2 in patients younger than 18. The urine output criterion is less than 0.3 mL/kg/h for at least 24 hours or anuria for 12 hours or longer.
When a patient's measures do not map to the same classification, the patient should be classified according to the highest-stage criterion.
“Nephrologists will now have to educate themselves about the classification system, which many have heard of in an abstract way but weren't using in clinical practice,” said Arif Khwaja, MD, PhD, Consultant Renal Physician at the Sheffield Kidney Institute and Honorary Senior Lecturer at the University of Sheffield in Sheffield, England.
“The question that will be asked is if this classification system is going to make a difference in outcomes. It will certainly make the detection of AKI more sensitive, but the jury is still out in terms of proving outcomes.”
The definition and staging recommendations are a combination of the RIFLE (Risk, Injury, Failure, Loss, and End-stage renal disease) and AKIN (Acute Kidney Injury Network) criteria for the condition.
“The whole issue of definition is controversial, recognizing that using serum creatinine as the marker does not tell you what GFR is,” said Paul Palevsky, MD, Chair of the NKF Spring Clinical Meetings session on KDOQI's response to the guideline. Dr. Palevsky is Professor of Medicine at the University of Pittsburgh School of Medicine and Chief of the Renal Section at the VA Pittsburgh Healthcare System.
“When RIFLE was developed, it was developed as an interim consensus definition, and I have a concern that it is now becoming the standard. There are many imperfections associated with it, so while not rejecting definitions, there are lots of caveats that need to be considered.”
Use of Diuretics, NAC
Diuretics were also considered in the guideline. The work group recommended that these agents not be used to treat acute kidney injury, except in the management of volume overload, or to prevent AKI, as there is no evidence that they reduce the incidence or severity of the condition (Recommendations 3.4.1 and 3.4.2).
“I think that most nephrologists would agree with this,” Dr. Khwaja said. “It is probably a sensible suggestion.”
The assessment of N-acetylcysteine (NAC), though, is not so clear-cut (Recommendation 4.4.3). The work group suggested using oral NAC, together with intravenous isotonic crystalloids, in patients at increased risk of contrast-induced acute kidney injury (CI-AKI).
“For contrast-induced AKI, there is still enough uncertainty and possibility of effect that we left open the potential for that indication,” Dr. Kellum said. “It's a drug that's possibly effective, cheap, and safe.”
Many, but not all, studies have shown NAC to have a protective effect on CI-AKI when it is administered before the onset of renal insult, the guideline noted.
In one such study, the rate of the composite endpoint of death, acute renal failure requiring temporary renal replacement therapy, or the need for mechanical ventilation was 7% with standard-dose NAC and 5% with double-dose NAC, versus 18% with placebo (Marenzi G et al: N Engl J Med 2006;354:2773–2782).
Other studies have found contradictory results, however, and there is no evidence that NAC influences mortality or need for renal replacement therapy in at-risk patients who have received contrast media.
“There are data that support NAC, and there are data that don't support it,” Dr. Singh said. “The committee came out in favor for use in CI-AKI, and that is an opinion, and when you have opinions, you have controversy. I tend to use NAC as an agent in contrast nephropathy.”
In the conference session on KDOQI's response to the guideline, Dr. Palevsky mentioned the Acetylcysteine for the Prevention of Contrast-Induced Nephropathy Trial (ACT), a large randomized, controlled trial conducted at 46 centers in Brazil that showed no benefit of NAC on contrast-induced nephropathy.
“While the ACT study was a large study, one of the things to consider is that it involved a population that would be considered relatively low risk, with only less than 16% having baseline serum creatinine greater than 1.5,” he said.
“The work group thought that the ACT trial is not the definitive negative trial and does not completely invalidate the use of NAC.”
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The Trouble with Guidelines
As is customary for clinical practice guidelines, the recommendations in the AKI guideline were graded. The strength of recommendation was described as Level 1 (we recommend), Level 2 (we suggest), or Not Graded. The quality of the supporting evidence was assigned a letter grade of A (high), B (moderate), C (low), or D (very low).
Just 14.8% of the recommendations were given the highest grade of 1A, while 63.9% were Level 2 suggestions, Dr. Khwaja noted.
“There is a rather wooly statement saying that all patients who have AKI should be managed as if they are at risk of CKD,” he said. “For many patients, that will be true. Many people appear to recover from AKI, and we don't know if it is cost-effective to follow the people up lifelong. There is an absence of any outcome data, so recommending that this happens is a bold statement.”
Dr. Singh's philosophy is to take a narrow approach to guidelines, he said.
“Guidelines tend to generate dogma, and guidelines change practice in ways of which subsequently obtaining evidence becomes more challenging.
“If, for example, a guideline says that you should use drug ‘x’ over drug ‘y’ or drug ‘x’ over nothing, it makes the performance of subsequent trials more challenging because the guideline is now saying that's what standard of care needs to be.
“I think guidelines should largely center around areas where evidence is settled or nearly settled rather than going in the direction of covering clinical evidence where either there is no evidence or weak evidence.”
Overall, the KDIGO guideline represents a constructive literature assessment, Dr. Khwaja said.
“In a way, the guideline tells us what we don't know in eloquent detail. It is a great review of the literature. I think some believe that this is what should be done—just offer recommendations when the evidence is good, and when it is not good, just say we don't know the best way forward.”
© 2012 Lippincott Williams & Wilkins, Inc.