Alan Bonder, MD, and Matthew Denker, MD, on Acute Kidney Injury in Cirrhosis
Dr Bonder and Dr Denker discuss the diagnosis and treatment of acute kidney injury among patients with cirrhosis of the liver.
Alan Bonder, MD, is an assistant professor of medicine at Harvard University Medical School and medical director of liver transplantation at Beth Israel Deaconess Medical Center in Boston, Massachusetts. He also serves as the Section Editor for Hepatic Diseases and Disorders on the Gastroenterology Learning Network. Matthew Denker, MD, is an assistant professor of medicine and practicing nephrologist at the University of Pennsylvania Perelman School of Medicine.
TRANSCRIPT:
Alan Bonder: Welcome, everyone, to another session for Gastroenterology Learning Network. I am honored to be joined by one of my coresidents in the past, Dr. Matthew Denker, who is currently an attending and an assistant professor of medicine at Penn. He is a nephrologist.
Today, we will discuss what would be the workup for acute kidney injury in a patient with liver disease. Matt, again, thank you. Matt, let me start with, this is a very common question for anyone who is in general gastroenterology.
A patient walks into your clinic, has a diagnosis of chronic liver disease/cirrhosis, and you do some basic labs as far as the routine workup, and you find that he has acute kidney injury. Does this patient, because he has liver disease, have hepatorenal syndrome?
Dr. Matthew Denker: This is a challenging scenario. Of course, many patients, most of what we see is acute kidney injury outside of cirrhosis. You have all the causes of acute kidney injury that could exist in noncirrhotics plus some of the cirrhotic-specific etiologies. Most of the time, it's not hepatorenal syndrome, but we would undergo an evaluation to try to discern what causes it might be.
Dr Bonder: Walk me a little bit through, what would you do? How would you manage this patient who shows up with a normal creatinine, now he has acute kidney injury? What would you do? Would this patient need to be admitted to the hospital? Can you manage this patient as an outpatient? What would you recommend?
Dr. Denker: It depends on the severity of their kidney disease, their kidney injury, and what the rest of their labs look like, in terms of electrolyte imbalance, their fluid balance. Are they struggling to breathe and requiring oxygen? Do they have uremic symptoms?
If their, let's say, their azotemia is very severe and affecting them to that degree, or is it more mild degrees of renal impairment? Most of the time, it could be managed as an outpatient. Is there hemodynamic compromise? What's their blood pressure? Are they able to perfuse their organs? Not necessarily a hospital admission, but it might lead to that.
Dr Bonder: When we trim it down to the patient with liver disease, also, the question, as gastroenterologists always ask ourselves, is if a patient does not have ascites or the patient does not have hyponatremia, can the patient have acute kidney injury leading to HRS, or we have to think about other etiologies?
Can you explain to me a little bit, what's the thought process with physical findings as well as physical exam in guiding your diagnosis of acute kidney injury?
Dr. Denker: The challenges of diagnosing hepatorenal syndrome are twofold. One, it's a diagnosis of exclusion, so there's not 1, 2, or 3 tests that will confirm the diagnosis. We have to exclude other factors.
Two, would be the evolution of the diagnostic criteria, which have changed over the years. In the 2007, I want to say, diagnostic criteria for HRS, patient with ascites is part of the criteria.
The hemodynamic compromise that comes about in the pathophysiologic mechanisms that predispose to HRS are triggered by portal hypertension. I don't think it can exist without ascites.
Dr Bonder: How about hyponatremia, is that also something required to diagnose someone with HRS with acute kidney injury?
Dr. Denker: I don't believe so. A poor prognostic sign, but I don't think you have to have it in order to say that the person has HRS.
Dr Bonder: Again, asking you, how do you work? We have a patient who has ascites, who is hypernatremic, and who has acute kidney injury. We, as comanaging the patient, we decided to admit the patient to the hospital. What would be his initial workup to determine, what's his etiology of his kidney disease?
Dr. Denker: Again, considering the broad differential of noncirrhotic conditions, most of what we see is prerenal or ATN causes of AKI. These patients may be on lactulose and having high stool output, they're on diuretics, maybe they didn't eat for a few days and could become prerenal.
They could have large-volume paracentesis. Again, the fluid shifts causing hemodynamic stress on the kidney and prerenal or renal underperfusion. It can have infections, so leading to ATN. Can take medications that lead to either ATN, for example, aminoglycosides or anti-inflammatories, the NSAIDs leading to AIN or antibiotics leading to AIN.
You have that bag of etiologies there. As well as, if there's large-volume ascites, abdominal compartment syndrome is certainly a consideration. Patients could have obstruction, so that would be picked up on imaging.
Considering all those entities, we would go through, obviously, a history and physical, looking at urinalysis and urine microscopy. Typically, at least classically, HRS was thought to have a bland urine, so absence of hematuria and proteinuria.
However, patients with underlying, for example, diabetic nephropathy could have HRS on top of their CKD. It's important to look at prior urine studies. The basics would be history and physical, medication list, and a urinalysis/urine microscopy in order to get the ball rolling, plus or minus imaging.
Dr Bonder: Let's keep talking a little more in detail about, for example, HRS. Is there any specific triggers, or anything that triggers acute kidney injury will be the same for someone who has HRS? This is thinking about a worse AKI. We call that HRS in a patient with liver disease. How would you differentiate between one and the other?
Dr. Denker: Can occur spontaneously. The classic triggers would be infections like SPP or a GI bleed could trigger HRS.
Dr Bonder: Tell me, when do you decide to, "OK, we're pretty sure this is a bland urinalysis. He doesn't have intrarenal disease. It's post. We rule out obstruction." When do we say, "OK, it looks fightable. Let's just start treating his HRS"?
When do you think it is the right course? At what time do we decide, "This is the right moment to do it"? Should we wait until the patients get a little but sicker, or should we wait until the patients need more renal replacement therapy? Can you comment a little bit on that?
Dr. Denker: There's no standard on when to start treatment, but ruling out prerenal injury first would be withdrawal of diuretics and volume expansion with IV albumin would be the starting point. Doing that for generally about 2 days, just to reverse prerenal injury, which is more common than HRS.
Some people have advocated for IV albumin not being for everyone, and maybe we should be directing therapy at their volume status, so looking at IVC collapsibility. Maybe some patients wouldn't respond and might worsen with IV albumin, especially if they've come into the hospital hypervolemic.
Typically, withdrawal of diuretics, IV albumin, if they don't respond after 40 hours of that, then initiating therapy for HRS. Obviously, after excluding other causes and if you have a high suspicion for HRS.
Typically, a low urine sodium because of the intense renal vasoconstriction that happens. Another, not necessarily diagnostic criteria, but a clue of hepatorenal syndrome.
Dr Bonder: How do you monitor response to treatment? I've heard from different nephrologists, maybe we'll focus on urine output, we'll focus in on the serum creatinine.
As you know, serum creatinine is not a good marker on patients with liver disease, so what do you guys think about, how do we monitor response in treatment for HRS?
Dr. Denker: The 2 in combination. You'd like to see improvement in renal function, improvement in serum creatinine, and an improvement in renal function. They usually go together. If you're going to see improvement in creatinine, you're going to see improvement in urine output, if the urine output had been low.
Again, classically thought to be oliguric AKI with HRS, but not necessarily. If the patient starts out nonoliguric, then remaining nonoliguric doesn't tell you much. If they are oliguric, you start to see better renal perfusion with treatments targeting for a higher MAP, then you're going to see more urine output and typically, the creatinine trend downward.
Dr Bonder: What time do you stop? I would say, "Is this creatinine normalizing?" Again, of course, the liver is not working, so what time would you say, "OK, it's time to get rid of the treatments that we have available and see if the kidney function will open up"? What's your comment on that?
Dr. Denker: Of course, these are all temporizing measures as well, because ultimately, you're just trying to buy time for a liver transplant. Typical treatment course, again, no standard here, and our therapies in the United States typically involve midodrine/octreotide combo, or if the patient is in the ICU, a norepinephrine infusion.
Again, vasoconstricted mechanisms to increase renal perfusion. Duration, typically about 1 to 2 weeks. If there's no response after a week, then the treatment is not effective, and futile, and maybe there's no sense in continuing it. Again, that's not standard, and some people would continue.
If the patient has improvement in renal function, they're able to safely leave the hospital, then some people might advocate for continuing outpatient midodrine. It's an oral therapy, it's easy to take, so it's all over the map, in terms of what you could do.
Alan: How about dialysis? We always ask the question is, "We are not offering dialysis, because the patient has cirrhosis." What's your point on dialysis in patients who have HRS? Is that something that you guys offer? Is that something that you will discuss with a primary team? How will you make that decision on who gets dialysis or who doesn't get dialysis?
Dr. Denker: Of course, the typical indications for whether to start dialysis, electrolyte disorders, acid base, and uremic symptoms, and volume overload. Again, what we're all taught starting from medical school through our training.
Whether to initiate depends on whether the patient is a transplant candidate, because outcomes are so poor in patients with cirrhosis and AKI that are needing dialysis who aren't transplant candidates. Survival is very poor.
If they're not a transplant candidate, then it involves multidisciplinary meetings with nephrology, gastroenterology and in palliative care. That would be very appropriate. If the patient is a liver transplant candidate, then dialysis would be certainly on the table and we would offer.
Dr Bonder: The last thing that I want to ask you, it was just recently published about terlipressin. Again, you mentioned the therapies that we have available in the US, but again, it was just recently published.
What do you think about the terlipressin as part of the new treatments? Is this going to buy us more time for transplant? Is this going to save some kidneys going into transplant? What's your perspective in this?
Dr. Denker: Time will tell. We don't know enough yet. Obviously, it just published last month in The New England Journal. The CONFIRM study is what you're referring to, and there have been other studies as well.
CONFIRM study was a placebo-controlled randomized trial. I don't believe we know how terlipressin matches up with our usual standard of therapies that we have available now. Of course, terlipressin, costly and not available in the United States currently, but better renal outcomes compared to placebo, in terms of reversal of HRS.
There was a creatinine improvement outcome there. That was a very sick population, MELD scores in the 30s and creatinine levels in the 3s. Reversal of HRS was improvement in creatinine down to a level less than 1.5.
There were some concerns raised about safety, in terms of respiratory failure and death from respiratory failure. I don't know, is the bottom line. Obviously, promising as opposed to placebo. Again, it's vasoconstrictive therapy, so maybe just improving the MAP is enough to increase renal perfusion.
Again, very sick population in the patients in that study. About 50% died within 3 months.
Dr Bonder: Again, maybe the message is you need to buy it some time to get them through a transplant. Maybe that's the bottom line.
Dr. Denker: Yes, transplant is the key. Again, you're just buying time with medical therapy.
Dr Bonder: If you want to summarize, what would be the home-take points for a general gastroenterologist on someone who has acute kidney injury with liver disease?
Dr. Denker: In general, there's a quick maybe trigger to, "Hey, should I be starting midodrine/octreotide now when the patient enters the hospital?" Of course, we go through our differential diagnosis keeping in mind other things.
It could be as simple as abdominal compartment syndrome and the patient improves with a paracentesis. Not everyone with cirrhosis and AKI has HRS. That's important to keep in mind. There is time to institute therapies, mainly volume expansion.
Again, if the patient needs it, again, prerenal, extremely common and there's usually some historical feature there, like decreased oral intake, vomiting, diarrhea. Then, improvement of the MAP with midodrine or if the patient's in the ICU with norepinephrine.
That will buy you time for the nephrologist to come on board and do their more extensive evaluation. Not everyone that hits the hospital needs treatment right away.
Dr Bonder: One very tricky question we always also get asked when there's an inpatient in the wards is, "When do we call nephrology?"
Dr. Denker: Great question. I don't have a good answer for you. We would like to be called early in the course and rather than at the point of someone needing dialysis. How early is too early? You'd like to maybe do something on your own, like order a urinalysis and maybe hold the diuretics and give albumin for a day.
If things aren't improved at that point, maybe get us involved. We may say, "Continue for another day," but trying something is helpful. Look, we're not opposed to seeing patients, so call us whenever you feel uncomfortable.
Dr Bonder: All right. Thanks, Dr. Denker. I appreciate your help. Hopefully, we'll have you again.
Dr. Denker: Sure, happy to.
Alan: All right, thank you.
