Addressing Pharmacokinetic Alterations That Occur in Patients Who Are in Acute Kidney Failure

At the 21st Annual MAD-ID Meeting in Orlando, Florida, Contagion^® sat down with Bruce A. Mueller, PharmD, professor of Clinical Pharmacy at the University of Michigan College of Pharmacy, who shared with us some of the pharmacokinetic alterations that occur in patients who are in acute kidney failure in the intensive care unit (ICU).

According to Dr. Mueller, "Patients with kidney disease in the intensive care unit have different pharmacokinetics than other individuals in the ICU who don’t have kidney disease. The differences between chronic kidney disease and acute kidney injury are greater than what we first thought. A clinician might look at a patient who makes no urine and because he or she had acute kidney injury, the clinician might think that you should treat them the same as if they had chronic kidney disease and made no urine. That would be a mistake. When I look at my outpatient dialysis unit and I see the typical patient who is there: they may have long-standing diabetes and hypertension, and they have not made urine for years, and they have a certain set of pharmacokinetics. Contrast that person to the person who is in the intensive care unit who was healthy yesterday, and had a bad thing happen to them—a car accident, sepsis, something bad happened to them—and now they do not make urine. They are a different person than the person who is in my outpatient dialysis unit and their pharmacokinetics are different as well. Let me give you some examples: Frequently in the intensive care unit in acute kidney injury, fluid overload is common. Because fluid overload is common, the volume distribution of drugs is going to be very different—particularly in the early stages of acute kidney injury while they are fluid overloaded—than the standard stable hemodialysis patient. Doses will likely have to be larger.

Another aspect that will be different is something that we cannot measure, and that’s perhaps most frustrating of all. That is: what is going on at the liver? It was only recognized in the early 1990s that the hepatic drug clearance in patients with acute kidney injury was vastly different than what it is in chronic kidney disease. I was involved in those first few studies and it was amazing. We investigated 2 drugs—vancomycin and imipenem—both drugs that we adjust for renal function. We are certainly worried about the nephrotoxicity associated with vancomycin; we are worried about the seizure potential with imipenem, and so it was important for us to reduce the doses in patients who needed that. If we look at vancomycin, we know that we adjust for renal disease, but no one thought to look at what’s going on at the liver. In fact, in healthy individuals, the nonrenal clearance, or liver clearance, of vancomycin is 40mL per minute. But, in end-stage renal disease, the liver clearance is only 6 mL per minute. Something happens to our liver in the course of kidney disease such that the hepatic clearance of vancomycin goes down substantially.

What is going on with patients with acute kidney injury? Yesterday, when they were healthy, they might have had a nonrenal clearance of 40mL, and now today, they have acute kidney injury and so is it down to 6mL per minute? In our published paper from 1991, we show that it’s not 6mL per minute, but it’s not 40 mL per minute anymore either. The longer you are in acute kidney injury, the worse your liver function gets in terms of how it clears vancomycin. We are lucky with vancomycin in that we adjust with therapeutic drug monitoring and we measure serum drug concentrations so that we can adjust for this. But, in general, in acute kidney injury, you have to give a higher dose than you have to give in end-stage renal disease when all other aspects are equal.

With imipenem, it’s a little scarier because you don’t have therapeutic drug monitoring to help you. In imipenem’s case, the normal hepatic clearance is 100mL to 120mL per minute. The hepatic clearance in end-stage renal disease is closer to 50mL per minute. What is it in patients with acute kidney injury? It’s not 50mL per minute. In fact, it’s closer to normal, about 100mL per minute. What does this mean? It means that the liver is metabolizing imipenem twice as fast in acute kidney injury than in end-stage renal disease, therefore, if you use the drug dosing recommendations which were derived from patients with end-stage renal disease, you are only giving about half as much drug as you should be giving. The problem is that you cannot catch that because we do not perform routine imipenem serum concentration monitoring in the United States. In general, my recommendation would be, if you are using imipenem in a patient with acute kidney injury, you need to be using twice the dose as what it says in the package insert. If you have a CRT patient who needs imipenem, don’t be hesitant to dose them 500mL every 6 hours because the liver is clearing more drug than you can possibly recognize.

And so, thinking about pharmacokinetic differences, we do not usually think about the liver because we cannot really measure anything, but that hepatic clearance and that volume of distribution are really 2 of the most important issues one can consider.

I think the final thing to consider is: What are you doing with a renal replacement therapy in the intensive care unit? Depending on what hospital someone gets sick in, they are going to receive a different renal replacement therapy. There are hospitals all over the world where hemodialysis is the number one renal placement therapy in the intensive care unit, and there are other places where continuous renal replacement therapies are used, and there are other who use hybrid therapies (ex: SLED) where they run for 8 to 12 hours a day, a little bit continuous and a little bit intermittent and consequently drug dosing gets very difficult, because half of the day you have a lot of clearance and then the other half of the day you don’t have very much clearance. Whatever you are doing in your institution, you need to understand what that is doing to the drugs because renal replacement therapies remove drugs. Most drugs have some fraction that is unbound and that is free to be removed. Most drugs are water-soluble; they are going to be removed. Therefore, you have to have a really good idea of what’s going on, the flow rates, and information from the literature to find the best evidence you can find. When all else fails, be aggressive on your dosing because we are probably underdosing most patients in the intensive care unit who are receiving renal replacement therapies.