Today we are (finally) going to tackle the third and final installment in the liver disease series. It’s time for hepatorenal syndrome (HRS)!!!

Really, we shouldn’t put that many exclamation points at the end of that sentence. HRS is no joke and not really something to be all that excited about.

By this end of this post, hopefully you’ll understand better why that is. And also maybe how to deal with it when it does arise.

So here goes.

We combined ALL of the posts in this Liver series AND our Kidney series into a single PDF. If you’d like a downloadable (and printer-friendly) version of this article, you can get one here

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WHAT IS HEPATORENAL SYNDROME?

HRS is the development of renal failure in patients with advanced liver failure in the absence of any identifiable causes of renal pathology. Forty percent of patients develop HRS within 5 years, and the mortality rate is HIGH - one estimate is 80% within 2 weeks.

Yikes.

But remember, we’re here to learn how to treat them so perhaps that mortality number is not so terrible.

FYI, if you haven’t read part 1 of this series already, you really should before you dive into HRS. This is because HRS is directly related to the pathophysiology of portal hypertension.

Left side: This is a kidney angiogram in a patient with hepatorenal syndrome. Note the severe vasoconstriction and lack of arterial filling. You can hardly see the blood vessels! Right side: This is an angiogram of the same kidney performed after th… — *Left side:* This is a kidney angiogram in a patient with hepatorenal syndrome. Note the severe vasoconstriction and lack of arterial filling. You can hardly see the blood vessels! *Right side:* This is an angiogram of the same kidney performed after the patient passed away. You can see all the blood vessels this time, demonstrating that the vasculature was actually fine, just not perfused. (Image)

The cliff notes…

Portal hypertension is the term for increased pressure in the portal vein, resulting from architectural changes to the liver’s structure. Portal hypertension leads to splanchnic vasodilation. This splanchnic vasodilation leads to the kidneys perceiving hypotension and decreased circulating volume. The kidneys freak out and activate the RAAS system and the sympathetic nervous system.

And bam, now you have vasoconstriction (along with many other effects described in part 1).

But vasoconstriction is what we want to focus on most in this post.

One of the blood vessels sucked into this web of vasoconstriction is the renal artery. And when it clamps down thinking it’s going to help the kidney get more blood flow by increasing pressure…it actually does the opposite. It can restrict blood flow to the kidneys so significantly that it causes kidney damage from lack of perfusion!

The human body is pretty cool, but sometimes it just #can’teven.

DIAGNOSIS AND CLASSIFICATION OF HEPATORENAL SYNDROME

As its name implies, in order to meet criteria for HRS, there needs to be both liver and kidney dysfunction. So the first 2 key points for HRS are a history of cirrhosis with ascites and a serum creatinine greater than 1.5 mg/dL.

After these 2 pieces, HRS becomes kind of a diagnosis of exclusion. This means it’s important to rule out other potential causes of the apparent renal dysfunction.

Does the serum creatinine improve after at least 2 days of diuretic withdrawal and volume expansion? Did the patient experience any type of shock? Are there other nephrotoxic medications? Is there evidence of parenchymal kidney disease, including proteinuria, hematuria, or an abnormal renal ultrasound?

If these other possibilities don’t pan out, then you’re likely headed down the HRS road.

Once on this road, it’s important to know there are 2 different classifications of HRS, very creatively named types 1 and 2. These types are not mutually exclusive, and some might even consider them to be on a spectrum, since type 2 can evolve into type 1 depending on what happens in the patient’s clinical course over time.

Acute hepatic injury may include: acute viral hepatitis, drug-induced liver injury (e.g. APAP), hepatic ischemia. (Image)

So now that we know how serious HRS is, what it is, and why it happens, the real question is this: what do we do about it?

MANAGEMENT OF HEPATORENAL SYNDROME

Let’s just cut to the chase. The real treatment for HRS – if we’re really talking about a long-term treatment – is liver transplant.

End of post.

Kidding…

But really, that is truly the only true treatment. As we explore some of the following measures, recognize that this section is “management” of HRS. Not “treatment”. That’s because everything else that we are going to discuss is targeted at buying time and mitigating damage until the patient might be able to get a new liver.

I told you. HRS is no joke.

Thinking about pharmacotherapy, there are really two big buckets of medications that can help:

Intravascular volume expanders

Here we’re really talking about albumin. There’s been a longstanding debate about colloid vs crystalloid volume expanders, so albumin vs saline. Basically, it makes sense to use albumin based on its properties as a volume expander, but there is almost no data to support it. And it is $$$. Only extremely small studies have found some slight benefit, but it also does not appear to do any harm to patients’ survival outcomes.

So despite its expensive price tag, albumin is usually the choice.

Dosing is still somewhat debated. (I mean, as stated above, we’re not even sure if we’re making the right choice by using albumin - let alone what dose is ideal!) Generally speaking, however, albumin 25% solution is infused at doses of 1g/kg on day 1, followed by 25g daily.

Most institutions also put a max duration on this therapy given the unclear benefit and high cost, especially if patients don’t show a positive response in a few days.

2. Vasocontrictors

Wait… I thought the problem was vasoconstriction! Why on earth would we give vasoconstrictors!??!

Go back to the pathophysiology. The kidneys are sensing splanchnic vasodilation. And the kidney-freak out that leads to the clamping down of the renal arteries is really due to that initial read of splanchnic vasodilation.

So if we can reduce the splanchnic vasodilation, aka vasoconstrict those vessels, maybe the kidneys won’t freak out so much.

So that’s why we use vasoconstrictors to treat a vasoconstriction issue.

Now we theoretically want to be a little picky about what blood vessels we’re vasoconstricting with our treatments. We don’t necessarily need every blood vessel in the body to constrict, and it would be lovely if we could, I dunno, target those splanchnic vessels…

Well, maybe we sorta can.

Vasoconstrictors for Hepatorenal Syndrome

Let’s look at our vasoconstriction options. They fall into 3 different classes: vasopressin and analogs, alpha adrenergic agonists, and somatostatin analog.

Vasopressin and its analog, terlipressin, act at the V1 receptors to increase systemic vascular resistance and mean arterial blood pressure. V1 receptors are located on the surface of vascular smooth muscle, and given they are G-protein coupled receptors (GPCRs), binding by vasopressin/terlipressin produces intracellular calcium. This calcium then binds to downstream targets like calmodulin to cause smooth muscle contraction.

Side note: it’s easy to get confused on the effects of vasopressin because (if you remember way back to physiology) it’s also known as antidiuretic hormone, or ADH. This effect of vasopressin is due to its effects on the V2 receptors, which are located on the kidney’s collecting duct surface. In this role, vasopressin leads to reabsorption of water from the urine due to increased production/migration of aquaporin channels. For more about how activity at the V2 receptors may have pharmacologic use, check out the vaptan class of medications.

Ok, back to vasoconstriction.

The unfortunate part about using vasopressin is that it’s not selective for any particular part of the vasculature. Even though we don’t really want to constrict blood flow in the periphery, guess what… you don’t really have a choice with vasopressin. So you may end up with tissue ischemia and subsequent necrosis. In terms of other organs, vasopressin can cause worsening cardiac output, myocardial ischemia, and/or cardiac arrhythmias.

Yeesh. No bueno.

So then there’s terlipressin, a vasopressin analog. This medication is more selective for the V1a receptors that are largely located in the splanchnic vasculature. So the thought behind this med’s use in HRS was to minimize vasopressin activity outside of the target area, hopefully maximizing therapeutic effect and minimizing safety issues.

For years, decades actually, terlipressin has been available outside of the United States. But if you try to look up this medication in LexiComp, it won’t be there. That’s because even after years of trials and experience in other places, it hasn’t passed the FDA’s muster for full approval. It only received orphan drug approval a few years ago, which is why there have been some recent clinical trials evaluating its use. More on this in a few.

Next there’s the alpha adrenergic agonists, which really in the case of HRS mean norepinephrine and midodrine.

Norepinephrine is a nonselective catecholamine that agonizes alpha receptors causing vasoconstriction. It also does agonize beta-1 receptors to some degree, which is why it is also responsible for some inotropic and chronotropic cardiac effects. (Remember, 1 heart and 2 lungs…so the beta-1 receptors are in the heart!). It is intravenous only and requires intensive monitoring and titration.

Then there’s midodrine. You can sort of think of it like a PO vasopressor… because it’s an oral medication whose active metabolite agonizes the alpha receptors. It’s dosed three times a day, which isn’t great for adherence…but it’s ORAL. Log that away.

The final vasoconstrictor is the somatostatin analog: octreotide. I’m not going to lie to you. I still don’t fully understand how this medication works - because it seems like it does a little bit of everything.

Endogenous somatostatin is a potent inhibitor of glucagon, insulin, and growth hormone, and it’s also a vasoconstrictor. It has affinity for 5 subtypes of somatostatin receptor (SSTR1-5), and these receptors are GPCRs that affect a wide array of mediators, including calcium, potassium, kinases, adenyl cyclase, cyclic GMP, phospholipase, and the list goes on.

One possible mechanism of octreotide is that it has the greatest effects on SSTR2 and SSTR5, which lead to increased intracellular calcium, smooth muscle contraction, and voila, vasoconstriction.

When you read the MOA section for octreotide on LexiComp. (Image) — When you read the MOA section for octreotide on LexiComp.

But yeah. It’s still a bit of a head scratcher when you look up octreotide and see all of its different indications.

So now you know a little bit about all the players up for the draft. But which one (or ones) do you pick for your HRS team??

Well, quite frankly, traditional vasopressin sounds like a bit of a disaster. We can do better.

For parenteral products, there used to be this longstanding desire to add terlipressin to the mix to replace norepinephrine. Norepinephrine is old, not selective for splanchnic vasculature, and can’t we just - by golly - do better? Shiny terlipressin was used everywhere else… At the risk of sounding whiny, why can’t we get that here??

Enter the primary lit.

In multiple (aka at least 5) separate randomized controlled studies, terlipressin has not demonstrated an advantage over good ol’ norepinephrine. One of the latest of these studies is a 2018 randomized trial conducted in India.

In this study, 60 patients with Type 1 HRS were administered either norepinephrine titrated to increase mean arterial pressure or urine output or terlipressin titrated in response to serum creatinine changes. The primary endpoint was reversal of the Type 1 HRS, meaning the serum creatinine return to <1.5 mg/dL. They also assess 30 day mortality.

Baseline characteristics were largely relatively balanced between groups, with a pre-intervention serum creatinine ~3-3.5 mg/dL. Although not statistically significant, the terlipressin responders seemed to improve slightly more quickly than the norepinephrine responders, although in the end the rates of HRS reversal were similar between groups (53% norepinephrine vs 57% terlipressin). None of the patients who responded died within the following 30 days after hospital discharge. As expected, norepinephrine was significantly cheaper than terlipressin.

Of course, this study is in contrast to a recently re-published 2020 trial by Arora et al. In this randomized trial originally published in 2018 that was also conducted in India, 120 patients with HRS were randomized to either norepinephrine or terlipressin. Although the dosing of norepinephrine was similar to the aforementioned study, terlipressin was given as a continuous infusion this time rather than intermittent boluses. The max dose was also 12mg/day instead of the previous 8mg/day. The primary endpoint was still reversal of HRS by day 14 with a secondary endpoint to assess 28 day survival.

Of note, renal replacement therapy was allowed (and discussed) in the second study. No mention of dialysis was made in the first. The patients were about a decade younger with a lower pre-treatment serum creatinine value of ~2 mg/dL in the latter study. Interestingly, the second study’s patients had a higher MELD score (~33 vs 30) and a lower baseline mean arterial pressure (~70 vs 80 mmHg) than the first study.

This second study demonstrated more rapid and higher rates of HRS reversal with terlipressin than with norepinephrine (40% vs 16.7% for reversal, p<0.004). They also saw less need for renal replacement therapy in the terlipressin group. Even 28 day survival was significantly better with terlipressin (48.3% vs 20%, p=0.001).

So what’s the deal? Why such disparate results?

Was it because the second population was noted to be acute on chronic liver failure (ACLF) patients, which were specifically defined as separate from decompensated cirrhosis? Their definition of ACLF seems difficult to tease out from decompensated cirrhosis, but perhaps there’s something to that devil in the details.

Was it because the second study population was younger with potentially better renal reserve? Fewer medical insults?

Was it due to the terlipressin dosing protocol as a continuous infusion rather than bolus doses?

Hard to say.

But what we’re still left with is that terlipressin isn’t available in the United States, and norepinephrine seems to do a pretty comparable (and much cheaper) job in most of the available studies. So norepinephrine it is for HRS necessitating parenteral vasoconstriction.

Now if a patient gets started on norepinephrine, are they married to it forever and ever until their kidneys improve or they get their liver transplant?

Gosh, let’s hope not. Because that could be a hot minute. And that’s a lot of titration, monitoring, fluid, and ICU time.

AMO is ready to fight for your kidneys. Much like this trio was ready to fight for the WORLD. (Image) — AMO is ready to fight for your kidneys. Much like this trio was ready to fight for the WORLD.

Enter AMO therapy. Or albumin, midodrine, and octreotide.

(Do y’all hear that dramatic hero music too?)

This 3 drug combination may serve as a bridge to liver transplantation. As opposed to norepinephrine-based regimens, this therapy is feasible to do in acute care settings because midodrine is PO TID, albumin is an intermittent (rather than continuous) infusion, and octreotide can be given as a subcutaneous injection TID. (Remember from Part 2 that octreotide may also be administered as a continuous infusion for other liver-related indications!)

Doses of both midodrine and octreotide are uptitrated as tolerated by the patient to try and produce an increase in mean arterial pressure of at least 15 mmHg.

In this 2009 study, AMO therapy was compared against a historical control group that did not receive AMO. The majority of patients had type 1 HRS. The patients who received AMO treatment had significantly longer transplant-free survival time compared to those in the control group. Btw, we’re talking median survival times of 101 days versus 18 days, so not even in the same ballpark. Plus, survival benefits were seen in both types 1 and 2 HRS.

So AMO it is until the patient’s renal function improves and/or a new liver arrives.

The Transjugular Intrahepatic Portosystemic Shunt (TIPS) Procedure

This post would be remiss if we didn’t at least mention TIPS. Yes, we’re mostly pharmacy brains on here, but it’s important to have a smidge of procedural knowledge for understanding our patients’ therapy plans.

Yes, liver transplant is the ultimate goal for end-stage cirrhosis patients. But when that’s just not going to happen anytime soon or a patient isn’t a candidate for transplant, sometimes we have to resort to a different recourse as a bridge to buy time: TIPS. This stands for Transjugular Intrahepatic Portosystemic Shunt.

TIPS is essentially bypass surgery for the liver. Think of it this way… When your cardiac vessels become blocked up with bacon, Bacon, BACONNNN, what happens? We go around them with CABG (Coronary Artery Bypass Graft) surgery. And voila, the heart receives blood again.

I know I just overly simplified a ridiculously amazing and complex procedure. But you get the idea.

In the case of the liver, the structural changes that lead to portal hypertension can’t really be rectified. (See Part 1 about the course of cirrhosis.) So sometimes we have to acknowledge that the damage is done and work on diverting blood flow around the damaged area.

The TIPS procedure connects the portal vein to the hepatic vein, effectively bypassing all the fibrous blocked areas in the liver. This should alleviate the back up of pressure known as portal hypertension, thereby mitigating the splanchnic vasodilation and hopefully ameliorating the subsequent complications of cirrhosis.

Then there’s also the reality. There’s not really all that much great data that TIPS actually lengthens the survival of patients with HRS. In the short term, it can lead to hepatic encephalopathy (due to release of built-up toxins PLUS less efficient clearance of toxins since blood is going around the liver rather than through) and peri-procedural bleeding.

That being said, there is evidence that renal function improves after TIPS, even if it may take up to a year to normalize completely. The hormone imbalances that perpetuate portal hypertension and its complications (aka RAAS and norepinephrine) also improve after TIPS.

This has been our procedural foray for pharmacists today. Other details we can leave for the non-drug brains…

Alright. So that’s HRS in a nutshell. Kind of. But at least hopefully you know more about how to recognize it and what to do when it is suspected. Thanks for making it all the way through this Complications of Cirrhosis series and dedicating some solid time to the liver!