My #DreamRCT Entry: The AKI-REPACE Trial / by Methods Man


Acute Kidney Injury (AKI) is a killer. Given two hospitalized patients, identical except for the fact that one has AKI, the AKI patient is anywhere from 3-7 times as likely to die during that hospitalization. AKI is costly in terms of life-years lost, but also in terms of hard currency hospital acquired AKI increases the average hospital bill by $9,000. Given that many patients with AKI will progress to require dialysis, the costs of AKI can become staggeringly high quite quickly. Its a good thing, then, that we have such effective treatments for acute kidney injury:


Figure 1: Kidney Disease Improving Global Outcomes (KDIGO) management of AKI.

The reactionary paradigm of AKI treatment dont make it worse has hampered progress in this field for decades. Many trials, including one by my team, have failed to demonstrate that specific interventions, targeted towards patients with early acute kidney injury, can prevent the catastrophic downstream consequences.

Maybethese 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.


Figure 2: A reminder of what angiotensin 2 does.

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 good renal care 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 pathologically linked to decreased perfusion in the renal medulla.

Blood flow in the nephron

Figure 3: Note that the efferent arteriole supplies blood (and oxygen) to the chronically hypoxic renal medulla.

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-Inhbition (AKI REPACE) trial, we will enroll patients with early acute kidney injury and randomize them to placebo or intravenous enaloprilat, a short-acting ACE-inhibitor. As creatinine is expected to increase more in the enaloprilatarm, 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:

Dream RCT

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 (ie no study drug at the next 6 hour time point, with repeat labs) to active treatment with IV calcium, insulin, sodium polystyrene sulfateand/or furosemide. We will treat hypotension with intravenous fluids barring an active contraindication such as pulmonary edema or unexplainedhypoxemia.

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 seven 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 sydnrome).

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 4301 patients in each arm a total of 8,602 patients. Accounting for loss to follow-up, we will target a total enrollment of 9000 patients.

Primary Outcome:All-cause mortality during the hospitalization.

Secondary Outcomes:Mortality at 30-days and one year. Dialysis as an inpatient, at 30 days, and at one 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-HaenzselChi-square testing to account for stratification, with a two-sided p-value of 0.05. We will not adjustfor 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, wedoom our patients to an overly-conservative, overly-cautious, and unambitious paradigm of AKI treatment.

If you like this #DreamRCT, come (virtually) fund it!