If you had unlimited resources, what nephrology clinical trial would you conduct? That's the big idea behind DreamRCT, a project of UKidney created by Joel Topf, MD, and Jordan Weinstein, MD, in partnership with 番茄社区. Vote for your favorite trial at
Acute Kidney Injury (AKI) is a . Given two hospitalized patients, identical except for the fact that one has AKI, the AKI patient is anywhere during that hospitalization. AKI is costly in terms of life-years lost, but also in terms of hard currency -- . Given that many patients with AKI will progress to require dialysis, the costs of AKI can become staggeringly high quite quickly.
It's a good thing, then, that we have such effective treatments for AKI:
The reactionary paradigm of AKI treatment -- "don't make it worse" has hampered progress in this field for decades. Many trials, including , have failed to demonstrate that specific interventions, targeted towards patients with early AKI, can prevent the catastrophic downstream consequences.
Maybe these trials are negative because we are ignoring a potent agent in the fight. A class of drug simultaneously loved and feared by nephrologists. A class of drug that we have decades of experience using (albeit in other venues). I present to you: angiotensin converting enzyme (ACE) inhibitors.
The physiologic effects of ACE inhibitors are well-documented. They are anti-hypertensive agents, acting to reduce the affects of angiotensin 2 on vascular smooth muscle. By preferentially reducing efferent arteriolar vasoconstriction, ACEs also decrease glomerular hydrostatic pressure (thus decreasing filtration fraction), and so increase creatinine.
It is the expected increase in creatinine that has led more pragmatic researchers to shy away from treating AKI patients with ACE inhibitors. In fact, one paper, that may or may not have been authored by me, labeled "cessation of ACE inhibitor" as a marker of "" in patients with AKI.
But there is every reason to believe that ACE inhibitors might be helpful in this population.
Acute tubular necrosis (ATN), the most common form of hospital-acquired AKI, is a disease .
The renal medulla is a chronically under-perfused environment, due to the need to preserve the high osmotic gradients necessary to concentrate urine. Low blood flow in this area means that oxygen tension is low, making the cells of the renal medulla particularly susceptible to ischemic injury.
ACE inhibitors, by reducing efferent arteriolar vasoconstriction, increase medullary blood flow, potentially restoring adequate oxygenation to these important cells in times of kidney stress.
In the Acute Kidney Injury -- Restoring Perfusion with ACE Inhibition (AKI -- REPACE) trial, we will enroll patients with early acute kidney injury and randomize them to placebo or intravenous enalaprilat, a short-acting ACE-inhibitor. As creatinine is expected to increase more in the enalaprilat arm, the primary outcome will be all-cause mortality.
We are acutely aware that the treatment we are proposing may carry certain side effects. These include hypotension, hyperkalemia, increased BUN, and creatinine, which may result in an increased risk of dialysis in the intervention group. There is also the idiopathic risk of angioedema. Through careful trial design, we have attempted to mitigate these risks as much as possible.
Study Details
Design: We will identify patients with AKI using an electronic monitoring system. After informed consent, they will be given the first dose of study drug according to the following treatment algorithm:
We will treat with study drug every six hours (barring adverse effects). We will continue treatment until renal function recovery (as defined by a return to 10% of baseline creatinine), death, discharge from the hospital, or 7 days from randomization. Treatment will continue during dialysis.
Protocolized therapeutic intervention: Anticipating the development of hyperkalemia and hypotension in the treatment arm, we will provide a standardized treatment algorithm for all patients. Initial treatment of hyperkalemia will depend upon degree of hyperkalemia and may range from expectant management (i.e., no study drug at the next 6 hour time point, with repeat labs) to active treatment with IV calcium, insulin, sevelamer, and/or furosemide. We will treat hypotension with intravenous fluids barring an active contraindication such as pulmonary edema or unexplained hypoxemia.
Inclusion criteria: Hospitalized patients with incident acute kidney injury as defined by a 0.3mg/dL increase in creatinine over 48 hours or a 50% increase in creatinine over 7 days.
Exclusion criteria: Allergy or previous adverse reaction to ACE inhibitor, life-expectancy (as determined by treating physician) of less than 48 hours, hypotension requiring treatment with two or more pressor agents, serum potassium ≥5.5 meq/L, or conditions that predispose to the rapid development of hyperkalemia (rhabdomyolysis, tumor lysis syndrome).
Sample size: We expect a control group event rate of 10% based on our prior studies. To achieve 90% power to detect a relative reduction in the risk of death of 20% (8% death rate in the intervention group) at a p-value threshold of 0.05, we will need to enroll 4,301 patients in each arm -- a total of 8,602 patients. Accounting for loss to follow-up, we will target a total enrollment of 9,000 patients.
Primary outcome: All-cause mortality during the hospitalization.
Secondary outcomes: Mortality at 30 days and 1 year. Dialysis as an inpatient, at 30 days, and at 1 year. Urinary and serum AKI biomarkers (of course). Doses of study drug received. Incidence of protocolized adverse event treatment.
Randomization: Performed in a 1:1 fashion, stratified by ICU status at the time of randomization.
Statistical methods: Mantel-Haenzsel Chi-square testing to account for stratification, with a two-sided p-value of 0.05. We will not adjust for factors that we discover are unbalanced between the treatment groups because that is just wrong.
In conclusion, the AKI-REPACE study will pave the way towards ending acute kidney injury by restoring perfusion to the renal medulla. Without high-risk, high-reward trials such as this one, we doom our patients to an overly-conservative, overly-cautious, and unambitious paradigm of AKI treatment.
, () is an assistant professor of medicine at Yale University, performing clinical research in kidney diseases. He also serves as a medical reviewer and commentator for 番茄社区. You can follow him @methodsmanmd on twitter or at .