Time Stamps

  • 00:57 Understanding the Pathophysiology of HRS
  • 03:42 How Portal Hypertension Traps the Kidneys
  • 10:32 Sorting the Differential of AKI in Cirrhosis Beyond HRS
  • 18:28 Hyponatremia and Urine Sodium in Advanced Cirrhosis
  • 24:04 Official Diagnosis and Evolving Criteria of HRS
  • 29:30 Albumin: When It Helps and When to Hold Back
  • 34:00 Recap and Future Directions

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Show Notes

Pearl 1 Pathophysiology of HRS

What are the biological and hormonal changes during cirrhosis that make you susceptible to HRS?

  • Biological changes: 
    • PART 1: Cirrhosis → Liver stiffness → Portal hypertension → Nitric oxide-mediated vasodilation 
    • PART 2: Total body volume is UP, but there is LOW effective circulating volume → Kidney “perceives” low effective circulating volume → RASS stimulated → Vasoconstriction → Even LOWER perfusion to the kidney!
  • NOTE: The kidney itself is undamaged, so if perfusion can be restored, the renal function will recover. As evidenced by HRS kidneys working again when put in other patients!

(Left is HRS, right is the same kidney after death without the vasoconstriction effects) 

  • Neurohormonal changes
    • The  RAAS system, sympathetics systems and catecholamines are causing vasoconstriction. 
    • Prostaglandins try to counteract the vasoconstriction in the kidney
      • The reason why are cirrhosis patients are so susceptible to NSAIDs (a prostaglandin inhibitor)
  • Change your mindset to think of HRS as AKI on portal HTN and not AKI on cirrhosis. 
    • Worsening portal HTN causes HRS, not just cirrhosis.
    • A stable compensated cirrhosis patient with no evidence of portal HTN CANNOT get HRS. 

Pearl 2 Differential Diagnosis 

How do you approach the differential diagnosis of AKI in someone with cirrhosis?

  • Clues from history and physical exam  
    • Pre-renal clues: HPI such as “increased BMs due to lactalose, or recent diuretic dose increase”
    • Compare the blood pressure to prior clinic/ hospitalization values 
      • If the blood pressure is elevated →HRS very unlikely. 
        • The average MAP of arrival to the ED in HRS patients is 76. 
    • Signs of worsening portal HTN (HRS clues)
      • More frequent paras 
      • SBP 
      • hyponatremia.
    • ATN clues
      • Shock
      • Muddy brown casts
  • What if its actually NOT pre-renal AKI, ATN, or HRS?
    • It WONT always be pre-renal, HRS, or ATN! Who is more likely to be in this group?
      • Patients with new blood and protein in UA, look for: 
        • GN (especially in patients with Hep B and C)
        • IgA nephropathy (can be secondary to cirrhosis)

Pearl 3 All about sodium

How do you use serum and urine sodium to help in the differential diagnosis of AKI in cirrhosis? 

  • Serum sodium 
    • Advanced portal HTN usually cause hyponatremia. How?
      • Low effective circulation volume -> high RASS and high ADH -> hyponatremia 
  • FeNa
  • Pre-renal, HRS, and ATN can all be under 1%. 
  • FeNa in HRS will be under 0.5% 
    • NOTE: Even if a patient is on a diuretic, RAAS pull for sodium reabsorption is so strong→  FeNA will still be low
  • Some labs can only report urine sodium under 20, so you can’t calculate a true FeNa: In these cases make sure the urine sodium is under 20. If over 20, that is NOT HRS!

Pearl 4 Diagnosis 

How do you diagnose HRS?

  • American Association of the Study of Liver Disease Guidelines (2021): 
    • Required a long checklist for the diagnosis of HRS 
  • Acute Disease Quality Initiative (ADQI) consensus statement (2024) and International Club of Ascites (ICA):
    • Two major changes to the diagnosis of HRS
  • Diagnosis requires absence of strong evidence of another diagnosis.
  • No need for 48 hour albumin challenge (more in Pearl 5)
  • How to diagnose HRS
    • Use clues from pearl 2 (history of volume loss, signs of worsening portal HTN, FeNa) to differentiate between HRS, pre-renal and ATN.

Pearl 5 All about albumin

Is a 48 hour albumin challenge always necessary to diagnosis HRS

  • NO  mandatory 48 hour albumin challenge to diagnosis HRS 
  • Recommended strategy of using albumin
    • If a patient is obviously volume overloaded
      • Avoid use of albumin
    • If a patient is obviously volume down, or you are unsure of volume status
    • If suspicion for HRS is high and the patient is not obviously volume down
      • No longer have to wait 48 hours to start HRS treatment.   

Transcript

Dr. Juan Carlos Q. Velez: I always found that pathogenesis fascinating. As a medical student and resident. I was always reading about it, how the failure of one organ ended up affecting the kidneys, and then I started as a fellow seeing patients and consults, and how tough those consults were, and how my attendings were also struggling. And there was just such a high degree of uncertainty, which led me to start reading more and more and more about it and became one of my clinical area of interest. 

Dr. Shreya Trivedi: That was Dr. Juan Carlos Velez, a Nephrologist at Ochsner health.  

Dr. Juan Carlos Q. Velez: Hi, I am Juan Carlos Velez. I am a nephrologist at Oschner Health in New Orleans.

Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. I am Dr. Shreya Trivedi, and I am joined by…

Dr. Noah Markewitz: Hi! I am Dr. Noah Markewitz, a PGY-3 internal medicine resident at Montefiore in the Bronx.

Dr. Shreya Trivedi: Todays episode is all about Hepatorenal syndrome, or HRS-AKI. And yes we will be referring to hepatorenal syndrome as HRS. 

Dr. Noah Markewitz: Yeah and this will be a two part episode, so today will be all about diagnosis, and next week will be all about treatment. Lets talk about the 5 pearls we will be covering today. 

Dr. Shreya Trivedi: Remember to test yourself, because the more you test yourself the deeper your learning gains. 

Dr. Noah Markewitz: Pearl 1 Pathophysiology of HRS

Dr. Shreya Trivedi: What are the biological and hormonal changes during cirrhosis that make you susceptible to HRS?

Dr. Noah Markewitz: Pearl 2 Differential Diagnosis 

Dr. Shreya Trivedi: How do you approach the differential diagnosis of AKI in someone with cirrhosis?

Dr. Noah Markewitz: Pearl 3 All about sodium

Dr. Shreya Trivedi: How do you use serum and urine sodium to help in the differential diagnosis of AKI in cirrhosis?

Dr. Noah Markewitz: Pearl 4 The official diagnosis 

Dr. Shreya Trivedi: How do you actually diagnose HRS?

Dr. Noah Markewitz: Pearl 5 All about albumin

Dr. Shreya Trivedi: Is a 48 hour albumin challenge always necessary to diagnosis HRS?

Pearl 1 Pathophysiology of HRS

What are the biological and hormonal changes during cirrhosis that make you susceptible to HRS?

Dr. Noah Markewitz: The first thing for us to really appreciate for HRS is to shift our brains not to think in terms of cirrhosis, but to think in terms of portal HTN. 

Dr. Shreya Trivedi: And so if we really need to shift our focus to portal HTN, then lets quickly remind ourselves how that portal HTN develops.

Dr. Nikhilesh Mazumder: Cirrhosis itself is actually just the scarring of the liver. So the more the scarring and inflammation or fat, any of those kinds of combination of things, depending on which kind of liver disease you have, the more that happens, the more that blood can’t get through the liver, the higher the venous pressures are in your abdomen and you start to build up portal hypertension. And so patients usually don’t present until either somebody notices something weird on imaging or they have a complication of portal hypertension. And then typically the most common complication of portal hypertension is ascites, which is where that pressure builds up so much that you start to leak the fluid into the peritoneal cavity.

Dr. Noah Markewitz: That is Dr. Nik Mazumder a hepatologist from the University of Michigan. 

Dr. Nikhilesh Mazumder: My name’s Nick Maunder. I’m one of the transplant hepatologists here at University of Michigan. My interests are in portal hypertension and the complications and physiology therein and using that to better treat our liver patients and get them better.

Dr. Noah Markewitz: Once someone develops portal HTN it is the body’s hormonal response that creates an environment that makes my favorite needly little organs, the kidneys, so susceptible.

Dr. Juan Carlos Q. Velez: So you start with a cirrhotic liver, sort of a stiffness, liver stiffness that leads to increased intra hepatic vascular resistance that this process of a hypertensive kind of liver and stiff liver, that leads to a maladaptive response outside the liver that is kind of the opposite. So there’s a maladaptive vasodilation peripherally in the splanchnic circulation and other vascular beds mostly driven by release of nitric oxide. So nitric oxide is kind of absent inside the hepatic sinusoids, and becomes very prominent outside to try to fight this liver cirrhosis state. And as a result, you get this peripheral vasodilation. So that is going to start seeing in a signal to your baroreceptors that control vascular tone to say, okay, we’ve got to fix that. So we’re going to activate a sympathetic nervous system. And we know that sympathetic nervous system has its own mediators, but also activates via beta adrenergic receptors, the renal angiotensin system. So you also get the renal angiotensin system amplified, and both the sympathetic and renin angiotensin system are going to lead to the state of trying to reabsorb sodium and water and vasoconstrict vascular beds.

Dr. Noah Markewitz: So to recap, because of the stiffness in the liver, the body initially tries to compensate by vasodilating. The vasodilation leads to a state of low effective circulating volume. So even if your patient is total body volume up, what the kidney is actually sensing is low perfusion. So when the sensed perfusion is low, the kidney will activate the RAAS system which will try and vasoconstrict.

Dr. Shreya Trivedi: And of course your favorite organ the kidney, is an innocent bystander to that cascade of events that lead to vasoconstriction!  

Dr. Nikhilesh Mazumder: Also in the seventies they did some crazy stuff. They transplanted a Hepatorenal syndrome kidney into another person after the patient with cirrhosis died and the kidney worked great. So a lot of these things tell us that the kidney itself is kind of working, it’s normal, it’s just not getting the blood flow. And it’s because of this weird physiology hepatorenal syndrome. 

Dr. Noah Markewitz: These studies are fascinating. One that I really loved looked at at the angiography of a patient with hepatorenal syndrome. Nothing was perfused through the renal artery. And then on autopsy, when the vasoconstriction was no longer at play, when they did the same angiography, the flow was perfect, the kidney is completely normal. We will put a cool picture in the show notes.

Dr. Shreya Trivedi: Really neat to see! So this all reiterates to me that its vasoconstriction from the hormonal cascade is what causes the problems. The kidney itself is actually fine. And its all starts from that awful portal HTN.

Dr. Noah Markewitz: You know, Shreya, that reminds me…I see a lot of patients who happen to have cirrhosis in their one liner, and when they get an AKI, I cringe when I read the note, and under the problem of AKI, the note says hepatorenal syndrome?

Dr. Shreya Trivedi: Yeah, I’ve seen that before!

Dr. Noah Markewitz: Yeah, its all the time. And I’m like they have compensated cirrhosis they don’t have complications of cirrhosis and so without that portal HTN, this is not HRS. Our final expert, Dr. Marina Serper a hepatologist from University of Pennsylvania, will drive this point home for us.

Dr. Marina Serper: Hi, I am Marina Serper. I am a hepatologist at the University of Pennsylvania. If you have compensated cirrhosis for whatever reason, let’s say you had hepatitis C and you were treated, you removed the etiology of liver disease, but you have stable cirrhosis, you can live in that state for 10 years and nothing would happen. You don’t have to be predisposed to hepatorenal syndrome because you don’t necessarily have portal hypertension, you don’t have worsening of your liver. 

Dr. Shreya Trivedi: So Noah you are telling this person with stable cirrhosis who has no evidence portal HTN on exam, or no ascites on POCUS, by definition they cannot have hepatorenal syndrome, because its portal HTN that starts off this whole cascade.

Dr. Noah Markewitz: Exactly! The key way I like to reframe HRS is that it is not AKI on cirrhosis but rather AKI on portal HTN. 

Dr. Shreya Trivedi: Oh, I like ring to that!

Dr. Noah Markewitz: Yeah. You can not have HRS without evidence of worsening portal HTN. It is the portal HTN that matters, not the cirrhosis. 

Dr. Shreya Trivedi: OH just to draw a connection, I can see that come up in acute liver failure? In acute liver failure, patients don’t have time to develop the portal HTN  to kick off that cascade to cause HRS. 

Dr. Noah Markewitz: Yeah so next time you see someone with tylenol toxicity causing acute liver failure in the ICU, if they have AKI, that is usually ATN, that is not hepatorenal syndrome.

Dr. Shreya Trivedi: Ah yeah, they don’t have time to develop the portal hypertension that would kick off hepatorenal syndrome. Ok, maybe the last thing before we close our pathophys section bc I had such a big ah-ha about why we don’t like giving NSAIDs to patients with portal HTN.

Dr. Noah Markewitz: Here we are talking about prostaglandins. NSAIDs work essentially by blocking the production of prostaglandins. 

Dr. Shreya Trivedi: And a reminder In HRS, we have all this vasoconstriction happening and so our patients are relying on prostaglandins to fight it as much as possible to keep the vessel open. 

Dr. Juan Carlos Q. Velez: And this is why patients with cirrhosis are so dependent on those prostaglandin fighting the situation. And this is why if you give an NSAID to a patient with cirrhosis is bad news because they’re in such a high prostaglandin state to defend themselves against a high catecholamine Angiotensin II state that the minute you drop a prostaglandin inhibitor essentially shut down renal circulation and go into an AKI faster than anybody else.

Dr. Noah Markewitz: To summarize pearl one cirrhosis is just a stiff liver. And when we think about hepatorenal syndrome, the physiology here is that because the liver’s so stiff, the body’s initially going to try and vasodilate. What the vasodilation does – the kidney is sensing low effective circulating volume, what that’s going to do is it’s going to cause the kidney to turn on the RAS system and vasoconstrict and the kidney is extremely susceptible to that vasoconstriction. We have good evidence to show that if we can reverse that vasoconstriction, the kidney will wake back up.

Dr. Shreya Trivedi: That’s awesome. I think is that we should really be thinking about Hepatorenal syndrome not as something that can happen if someone has compensated cirrhosis, but it’s really going to be in a patient who’s developing an AKI on portal hypertension as the lovely future nephrologist, Noah, says.  

Pearl 2 Differential Diagnosis 

How do you approach the framework for differential diagnosis of AKI in someone with cirrhosis?

Dr. Shreya Trivedi: Lets use all that pathophys to get into the differential. So you have a patient with a Cr bump who has cirrhosis, how do you start to unpack what is driving that AKI?

Dr. Juan Carlos Q. Velez: They teach us that it’s 85% of the time the diagnosis is in the history, and it applies to cirrhosis too. Patient comes in, they were increasing the diuretics because of ascites. Patient was urinating more and became a little hypotensive. That’s a pre-renal  hint right there. Somebody comes with lactulose increases and comes with seven bowel a day because of hepatic encephalopathy prevention, things are very clear that you got to think it, pre-renal states is the first option.

Dr. Shreya Trivedi: This sounds similar to typical AKI work up. So if we have a good history for pre-renal it is likely pre-renal. 

Dr. Noah Markewitz: And sometimes the story is pretty good for ATN. For example a patient who has septic shock and AKI, that is likely going to be ATN.

Dr. Shreya Trivedi: Right those situations make sense. But the thing that trips me up is what are things should clue us about hepatorenal syndrome?

Dr. Noah Markewitz: Lets unpack that. Lets start with vitals. In theory a patient with HRS is in a very vasodilatory state and we would expect the blood pressure to be lower than normal. Not low enough to the point that we are worried about shock, but on the lower side. 

Dr. Juan Carlos Q. Velez: Okay. I’ll look at the vital signs immediately. Okay. If I have a blood pressure of 172 over 82, I mean I know that that’s not going to be HRS, it’s just not possible. It doesn’t fit. 

Dr. Shreya Trivedi: So with high BPm HRS is out. 

Dr. Noah Markewitz: Not so fast Shreya! But we cant be tricked and think HRS can only be with a low BP. It is all about relatively low compared to the patients normal.

Dr. Juan Carlos Q. Velez: If you look at the meta-analysis that we published in 2011, that we compiled over 20 clinical trials of HRS. The mean, right, the average mean arterial pressure on arrival was 76 millimeters of mercury, 76. So you don’t have to or necessarily have a MAP of 62 to think HRS. 

Dr. Shreya Trivedi: Great, so just to put this into context, what if we have a patient with MASLD who’s coming in with an AKI and BP of 120/80 but we look back at old clinic blood pressures and see their BPs are usually 160/90. That should raise some concern for a HRS.

Dr. Noah Markewitz: Right so even though a blood pressure of 120/80 is normal, it is relatively low. So after the blood pressure, the next thing to do is of course look for signs of worsening portal HTN, because throwback to pearl 1 – HRS is all about portal hypertension.

Dr. Marina Serper: I eyeball the patient. And I do think that the rubric of generally compensated decompensated or portal hypertension, no portal hypertension is very useful. So I look at the physical exam. So is this patient muscle wasted? Do they have a protuberant abdomen? Do they have spiderangiomata, do they have bulging flanks? Does this appear to be a decompensated patient? Then I think more likely this could be hepatorenal physiology, at least.

Dr. Juan Carlos Q. Velez: For instance, documentation of spontaneous bacterial peritonitis, and the literature is very clear that that’s one of the most established precipitating factors for HRS. So I’m going to look for that. And then is this patient coming from frequent paracentesis that they were monthly. Now were biweekly, now they’re weekly. So that’s telling me some progression of the portal hypertension.

Dr. Shreya Trivedi: Alright, so whether its on exam or chart review, we are looking for signs of worsening portal HTN. And on the flip side, if we don’t see any signs of portal HTN the diagnosis can’t be HRS. 

Dr. Noah Markewitz: So far we have just been talking about HRS, pre renal, and ATN. But its always humbling to be reminded that it isn’t just those 3 in the differential for AKI in cirrhosis. 

Dr. Juan Carlos Q. Velez: I think the majority of the literature in HRS, AKI, and cirrhosis has  concentrated into the idea that it is a triad of prerenal, ATN, and HRS. And they have tried to sold us this story of a three-way path, that there’s only three options. Anywhere between five 10 or even 15% of your patients may have something else. That is not any of those three. And I take that very seriously because I feel like that’s our role in nephrology. We don’t want to miss a GN that could have a completely different approach. So most of the times there will be a UA on record before we get consulted. And I’m going to look at a UA. There’s any evidence of proteinuria, hematuria, leukocyturia, those three things I’m going to look. 

Dr. Noah Markewitz: As a rule of thumb, in HRS you would expect see a bland UA, so no proteinuria, RBCs, no casts.

Dr. Juan Carlos Q. Velez: If I see the urinalysis showing those parameters, my next step is going to be go back to the history. Does this guy has hepatitis B, hepatitis C, oh look, there’s a million viral loads of hepatitis B two weeks ago, boom, my suspicion for hepatitis B associated GN is going to increase. And then we also know that patients with cirrhosis are predisposed to develop secondary IgA nephropathy, so that independently hepatitis B and C, I have that in my radar. 

Dr. Noah Markewitz: So so far, we have the big three of pre-renal, ATN, and HRS, we have a new glomerular process and then next on the differential, if we you have a patient with tense ascites you should always think about abdominal compartment syndrome. And that can be usually fixed with a large volume paracentesis.

Dr. Shreya Trivedi: That reminds me of a good rule of thumb in these patients. It’s always good to get a bladder scan, right? We don’t want to go down a rabbit hole and miss a simple post renal AKI. 

Dr. Noah Markewitz: There is one more feature that is really helpful in narrowing your differential diagnosis. That is sodium. In fact it is so helpful we are going to dedicate our entire next Pearl to sodium.

Dr. Shreya Trivedi: Yeah so before we move onto sodium, lets recap Pearl 2 on differential diagnosis of AKI in cirrhosis. Initially think of is similar to our typical AKI work up. Right? If their story is concerning for pre-renal -increased BMs due to lactulose its probably a pre-renal AKI. A patient with sepsis shock is likely to have ATN. And of course don’t forget about post-renal causes of AKI in pts with cirrhosis.

Dr. Noah Markewitz: And what makes the special AKI on cirrhosis, we have to think about this other diagnosis – HRS. Remember it is an AKI on portal hypertension. But if we are seeing signs of worsening portal HTN such as worsening ascites, more frequent paracentesis or SBP, that should trigger us to think about HRS. The opposite there is also true. If there is no ascites it isn’t HRS, period.  

Dr. Shreya Trivedi: You love that point! And then in patients who have a history of Hep B Hep C or have any blood or protein in the urine we should at least think about glomerularnephritis.

Pearl 3 All about sodium

How do you use serum and urine sodium to help in the differential diagnosis of AKI in cirrhosis. 

Dr. Noah Markewitz: So in the reasoning process of what is causing that AKI in the patient in cirrhosis, I wanna argue the most important diagnostic factor we need to talk about is sodium. Like most things in life, it always goes back to sodium. 

Dr. Shreya Trivedi: Very great point! So as a throwback to the hyponatremia episode, patients with portal HTN and decompensated cirrhosis have decreased effective circulating volume. That sense low effective blood volume is so low that it only turn on RAAS but also ADH release. And in high ADH states that causes hold onto free water and leads to hyponatremia.

Dr. Juan Carlos Q. Velez: At advanced cirrhosis, usually as a state where the probability of severe hyponatremia increases, sort of a compensated cirrhosis is not going to have a sodium of 118. That’s typically a decompensated cirrhosis, a high ADH state, it’s a high ADH state, so that’s going to be significant hemodynamic derangement. If you have a creatinine that is 3.2 and a sodium is 132 versus a creatinine 3.2 and a sodium of 118, I’m going to, okay, the 118 guy sounds like he’s a more advanced portal hypertension, advanced cirrhosis state.

Dr. Noah Markewitz: The point here is if you are intravascularly depleted enough to have developed HRS, by definition you must also be overproducing ADH and therefore, be a little hyponatremic. So we can think of the lower sodium as a correlate to worsening portal HTN.  And that is just the power of the serum sodium, we can get a lot more information from the urine sodium.

Dr. Shreya Trivedi: Yeah, definitely. And then I guess in thinking about AKI, we often get a fractional excretion of sodium, AKA FeNa, but I don’t know, is there any utility in getting that in open portal hypertension. I mean these patients, their urine sodium is always going to come back less than 20. Right? That portal hypertension, the patient’s always in this vasodilatory state and RAAS is cranked up. The body wants to retain as much sodium as possible. Yeah, urine sodium is always going to come back less than 20. Right? I’m curious, should we just ignore that FeNa and just skip that part in the workup?

Dr. Juan Carlos Q. Velez: We need to shift the threshold way down to the point that the classic cirrhotic is going to have a low FeNa, but in HRS is usually extremely low, almost another magnitude of low. So that’s why when I get a urine sodium, I still like to get a urine creatinine to get a sense of the FeNA. And bottom line is that yes, even ATN patients are going to have low FeNa, but it’s probably going to be like a 0.6%, not 0.08%.

Dr. Noah Markewitz: So lets back up. Where normally a FeNA of over 1% is consistent with intrinsic and under 1 percent is consistent with pre-renal. In cirrhosis we shift this framework. Every FeNa is going to be low. But, for the the AKI to be from HRS, we want a FeNa not to be less 1% but like 0.1%. 

Dr. Shreya Trivedi: And let me say it in another way to make it stick. We need to pay attention to the decimal point and the extra zero. If we get a FeNa back for a patient with portal hypertension and it is 0.06%, yes – it can be low enough to be HRS. But if it comes back and is 0.6% in a patient with portal hypertension, then its not HRS and might be ATN or something else. Again were talking about a whole magnitude of 10 difference.

Dr. Noah Markewitz: To recap, If the FeNA is <0.1% it is virtually certain to be HRS. Something like 0.2 or 0.3% does not rule it out or in. If it is >0.5% it is extremely unlikely to be HRS.

Dr. Shreya Trivedi: Now that I’m thinking about I’ve worked at a place where lab can only report urine sodium down to “under 20” making it impossible to calculate an accurate FeNa. What do we do then?

Dr. Noah Markewitz: Thats a great question. If that is the case the urine sodium can still be helpful. If the urine sodium is NOT less then 20 then HRS is ruled out. You will not have HRS with a urine sodium >20.

Dr. Shreya Trivedi: Ah so we don’t have a percentage but we have some kind of threshold to rule out HRS and something is better than nothing. Well what about if they were on a diuretic, how do we interpret that urine Na in these patients with portal hypertension?

Dr. Juan Carlos Q. Velez: And sometimes they tell me, well, the patient is on spironolactone. Well, let me tell you, the patient is HRS. The kidneys are not going to care if you are on spironolactone right? You’re just not going to respond to the point of having a urinary sodium of 40. Otherwise, the kidneys are fine at responding to the diuretic. So no, if a patient has a urinary sodium of 42, that is extremely inconsistent with HRS.

Dr. Noah Markewitz: So in HRS, all those hormonal changes make the drive for sodium reabsorption so strong that even on a diuretic, that causes you to pee out sodium, the urine sodium will be less than 20. Diuretics don’t matter. 

Dr. Shreya Trivedi: That is a great point. And I guess the clinical takeaway here is that I don’t have to wait until the diuretics are out of someone’s system to interpret the urine sodium. So that’s awesome. And so let’s summarize all things about the sodium. In Hepatorenal syndrome, We have high ADH state and so the serum sodium is going to be low and then also in Hepatorenal syndrome because of RAAS on that urine, sodium will also be low.

Dr. Noah Markewitz: And that urine sodium isnt just gonna be low, its gonna be really low. A FeNa of under 0.5% is suggestive of HRS. If the lab can only report a urine sodium of “less than 20” then the best you can do is make sure the urine sodium comes back as less than 20 before thinking about HRS.

Pearl 4 Diagnosis 

How do you diagnose HRS?

Dr. Noah Markewitz: Now we get to the fun and controversial part of this episode. The official diagnosis of HRS.

Dr. Shreya Trivedi: We first have to talk about this idea of an albumin challenge. There was a formal checklist to make the diagnosis of HRS. Reading off the (American Association of the study of liver disease) 2021 guidelines to diagnose HRS you needed cirrhosis with ascites, diagnosis of AKI, absence of shock, no recent use of nephrotoxic drugs (no recent IV contrast), no signs of structural kidney injury on ultrasound and no response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin.

Dr. Noah Markewitz: I don’t know about you Shreya but I don’t think I have ever seen a patient who has NO nephrotoxic meds. They all are on antibiotics or NSAIDS, or got IV contrast for a CT scan in the ED. So the criteria is very hard to meet. But the general idea with the albumin is to rule out pre-renal. In pre-renal disease, The Cr should get better if you stopping diuretics, and give albumin.  

Dr. Shreya Trivedi: So if the Cr doesn’t go down with albumin for 2 days you ruled out pre renal and then would need to differentiate between HRS and ATN. We can use a urine sodium after 48 hours of albumin challenge to help us differentiate HRS vs. ATN.

Dr. Noah Markewitz: If it is true HRS the urine sodium will remain low because of the high aldosterone state. If it is true ATN the urine sodium will be high since it ATN its more of a tubular injury and not aldosterone driving the AKI.

Dr. Shreya Trivedi: And just to say it out loud. Because we’ve ruled out pre-renal over the two days of albumin challenge and it didn’t get better, when you do get back that urine Na after 48 hours of albumin it can only be HRS. Now this makes me think about the idea of a 2 day albumin challenge. I don’t know about you, but I have had to many patients where it just didn’t feel right and I am wondering. Do we have to give 2 days of albumin? 

Dr. Noah Markewitz: Yep and that gets the controversial part. This kind of one size fits all approach has problems. Also so there’s has been a movement to change the way we diagnose HRS, particularly with two major changes.

Dr. Juan Carlos Q. Velez: In 2024 in March we published this. So there’s a big meeting we had in San Diego, a group of intensivists, hepatologists, and nephrologists. Let’s try to revisit this definition. And the conclusion was to remove all those criteria, summarize and replace it by a statement that says that HRS should be the diagnosis in the absence of a strong evidence of any other explanation. That’s it. Obviously a patient comes with fluid losses by history, you give him albumin and gets better. Boom. That’s pre-renal. That’s very simple. What would be strong evidence of ATN, urinary sodium of above 20 on arrival. That’s already strong evidence against HRS. That is FeNa above 0.7, 0.8%. That is too high. That is strong evidence of ATN already. 

Dr. Noah Markewitz: So to reiterate, the 1st major change is HRS is no longer diagnosed by that checklist. HRS is diagnosed when there is an absence of strong evidence against any other explanation. That is it. 

Dr. Shreya Trivedi: And so as a quick recap, we do have some labs that can clue us in that HRS is not going on. 

Dr. Noah Markewitz: So what would be strong evidence against HRS? We have talked about a lot of these. Urine Na >20 that is more likely ATN. If the FeNa is over 0.5 that is not HRS. If the story sounds pre-renal then it is probably pre renal and we should treat it as pre renal and not talk about HRS

Dr. Juan Carlos Q. Velez: What else is a strong evidence of against HRS patient comes with a serum sodium of 144. What? That’s not HRS. How is that going to be possible? Right? Again, those are not going to be on your definition when you go to UpToDate, but I’m just you answering your question. Those are the things that to me have now been replaced by this bold statement that in the absence of strong evidence of alternative explanation.

Dr. Shreya Trivedi: So to reiterate in classic HRS, we should not be seeing normal-high serum sodium. What is that? As a quick through back, in HRS the kidney senses they are so volume down that ADH is up and would contribute to some degree of hyponatremia.

Dr. Noah Markewitz: One other thing that is helpful is urine microscopy. Specifically greater then 10 muddy brown casts per high powered field is very likely to be ATN and is strong evidence against HRS. 

Dr. Shreya Trivedi: It is important to note that in real life sometimes it isn’t always this clear. The urine sodium will be low, but there will be some muddy brown casts, and it will be hard to call between ATN and HRS. And in a lot of these situations, all you can do is make your best guess. 

Dr. Noah Markewitz: Yeah, HRS is tough! Differentiating between HRS and ATN is hard and that’s why were making this podcast! Let’s recap Pearl 4. HRS should no longer be diagnosed by the formal checklist. The diagnosis has been replaced by a statement that HRS is in the absence of strong evidence of any other diagnosis. 

Dr. Shreya Trivedi: So does that mean we don’t have to do an albumin challenge every time now?

Dr. Noah Markewitz: And that Shreya is a great segway to pearl 5.

Pearl 5 All about albumin

Is a 48 hour albumin challenge always necessary to diagnosis HRS

Dr. Noah Markewitz: And this brings us to the second major change, it is no longer mandatory to give every patient 48 hour albumin challenge.

Dr. Shreya Trivedi: Oh thank god. It just felt so wrong with some patients!

Dr. Juan Carlos Q. Velez: We have a patient that comes in that was going to the hepatology clinic for frequent paracentesis and was requiring, as I described earlier, first was once every six weeks, now is every two weeks. And now it’s coming every week for paracentesis and shows up to the emergency room because the wife look at her husband’s like, you look like a balloon about to explode. And they come to you in the ED and they say that they have gained 13 kilograms despite the paracentesis and despite the diuretics. And you get an x-ray and it has hydrothorax and it’s got peripheral edema all the way to the hip and ascites and tense abdominal wall edema. How on earth you’re going to give albumin challenge to that patient? Think about it. So this is what you have been telling us historically, and this is just not an appropriate approach to just put everybody on the same bucket. Essentially give albumin, close your eyes, let’s come back in 48 hours. Did you get better? No, that’s not the approach. So my approach to albumin is in the presence of a clinical history that suggests volume depletion or in the absence of elements that suggests ongoing hypervolemia, go for the challenge. And essentially it looks dry, sounds dry, give albumin. If the patient is overloaded visibly, you stay away from albumin. If you’re kind of in a gray zone, you’re not sure, go ahead. It’s probably safe to try it. 

Dr. Shreya Trivedi: Okay takeaway – if a patient with cirrhosis and AKI is coming in with a story of pre-renal, yeah, sure give albumin. If the patient looks like  volume overloaded and we are worried about respiratory compromise, albumin isn’t going to help them.

Dr. Nikhilesh Mazumder: About eight to 11% of patients who get albumin with cirrhosis have flash pulmonary edema, and that’s often deadly, whether it being treated for sepsis or whatever you’re doing.

Dr. Shreya Trivedi: Quick caveat to that statistic of 8-11 percent, that was in patients with cirrhosis and sepsis, not HRS, so a little bit different. But the point is that albumin does not come without risks. 

Dr. Noah Markewitz: Exactly, we we can’t just give albumin like candy in every patient with AKI. We will talk about this more in Part 2 next week.

Dr. Nikhilesh Mazumder: And so knowing your patient’s intravascular volume status before you give them extra fluids, I think is the right next move. And so I think it’s reasonable to try albumin if you’re not sure or if you don’t see signs of volume overload. But I think it’s a little bit riskier and maybe even dangerous to just give albumin to everybody.

Dr. Shreya Trivedi: It definitely helps me to hear multiple people agree on something that used to be a dogma like albumin for 2 days in everyone with questionable hepatorenal syndrome.

Dr. Noah Markewitz: It is also good to hear even experts say its sometimes a hard call based on your best guess on what their intravascular volume status is.

Dr. Shreya Trivedi: Yeah definitely. If we do give albumin to a patient that we aren’t sure between HRS and pre-renal vs something else, do we still have to wait the FULL 48 hours before we call it HRS and possibly start treatment that would really help them?

Dr. Juan Carlos Q. Velez: What we said is you give albumin to a patient today, creatinine is 2.2 and the next day is 2.3 or 2.4 or 2.5. Are you going to tell me that after giving 100 grams of albumin and the creatinine went up, you’re going to give a second day and it’s going to be the inflection point is going to come down? No. Now, if the patient had a creatinine 2.1 and you gave albumin and it came down to 1.9, of course give it another day and give it another day and give it maybe 72 hours, maybe whatever it takes to get the resolution of the AKI. But the idea is that you need 48 hours to determine if it is going to work. I don’t agree with that at all. So I wanted to mention that because it has come out in some of the GI journals and I wasn’t really agreeing with that.

Dr. Noah Markewitz: Those trends in Cr are really helpful. So if the Cr the next day doesn’t budge at all AND we gave really aggressive albumin, then we should probably think about HRS on the sooner side. And this is important because HRS has a very specific treatment. That treatment will be the focus of the entire second part of this podcast next week.

Dr. Shreya Trivedi: So lets recap all things about diagnosing HRS. The rules have become less rigid and what we need to prove is that there isn’t an alternate diagnosis. To clarify, there is still a role for albumin. It  will treat pre-renal AKI in cirrhosis. However, we don’t need to wait 2 full days to see if it works or not. If the AKI is still not getting better than you are left with HRS or ATN (two things that are managed differently) and the urine sodium can help distinguish between the two. In HRS we expect a low urine sodium since aldosterone is at play. In ATN though, we have tubular injury and your kidney will not reabsorb that sodium and we will get a urine Na >20 in ATN.

Dr. Noah Markewitz: And that’s a wrap for today!

Dr. Shreya Trivedi: And if you found this episode helpful, our ask is to share with your team and colleagues and share it with someone else since HRS can be really tough! Stay tuned for our next episode on all things hepatorenal syndrome treatment. 

Dr. Noah Markewitz: Thank you to our reviewers, Dr. Tapper and Dr. Belcher and as always, opinions expressed our own and do not represent the opinions of any affiliate institutions. Thank you and take care.

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