Tag: Hepatorenal syndrome

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Cardiorenal syndrome

On the first Friday of every month I give a lecture to the residents at St. John Hospital and Medical Center. I like to do an electrolyte lecture but for March the chief resident asked me to talk about cardiorenal syndrome. In researching the lecture I came across this article by Claudio Ronco.

The article defines cardiorenal syndrome as any condition with simultaneous kidney and heart failure. He then goes on to subdivide cardiorenal syndrome into 5 types:

  1. Acute heart failure causing acute renal failure
  2. Chronic heart failure causing chronic kidney disease
  3. Acute kidney injury causing any type of acute cardiac dysfunction (including arrhythmia)
  4. Chronic kidney disease causing any chronic cardiac disease
  5. Any systemic condition that causes renal and cardiac dysfuction (e.g. sepsis)

This is terrible. Cardiorenal syndrome used to signify the unique cause of acute kidney injury where the decrease in function is due to apparent volume depletion in a patient that obviously overloaded. It named the only scenario where acute kidney injury responded to diuresis. It was unique and specific. Ronco comes along and says, yes I like your version of cardiorenal syndrome so I will make it type 1 in my new all purpose definition of cardiorenal syndrome. Now whenever there is cardiac dysfunction and simultaneous kidney dysfunction we can just call it cardiorenal syndrome.

It doesn’t have to be this way look at the example of hepatorenal syndrome. The syndrome does not refere to just any situation with simultaneous renal and liver dysfunction. It is a very specific diagnosis that only occurs with chronic liver disease and ascites. The patients must be oliguric, there is no non-oliguric HRS. Patients must be sodium avid and unresponsive to fluids and albumin. Additionally the patients cannot have laboratory or imaging evidence for an alternative cause of renal failure. Because of this definition hepatorenal syndrome identifies a very specific disorder, with a specific pathophysiology and unique prognosis and treatment options.

Ronco takes the beautiful and evocative name cardiorenal syndrome, strips it of all specificity and then tries to restore it by tacking on five different types. The fifth type 5 is the one that makes my brain explode. Sepsis, really? Acute kidney injury from sepsis that happens in the same patient who also suffers from sepsis induced cardiomyopathy should now be considered to have cardiorenal syndrome? Ronco is a man who has spent his life studying sepsis and acute renal failure, I can’t believe he is actually referring to that condition as CRS type 5.

I’m not buying what Ronco’s selling. Cardiorenal syndrome begins and ends with type 1 for me.

FYI: Here is the lecture (Keynote, PDF). It still needs some work. I’d like to add a section on ultrafiltration and I need to include the NEJM article on furosemide that was published yesterday.

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Hepatorenal syndrome Journal Club

Journal club today reviewed this article on the treatment of hepatorenal syndrome (HRS) with terlipressin. What a breath of fresh air in the field of HRS, a real randomized double blind placebo controlled trial!

Terlipressin is part of the new wave of HRS that focus on splanchnic vasoconstriction to reverse one of the initiating events in the pathologic cascade that results in HRS. I have been using the combination of octreotide and midodrine to exploit the same therapeutic target. I have had mixed results. I am not aware of any prior controlled trials of this therapeutic target.

Enrollment criteria:

  • Age ≥18
  • Liver disease
  • Doubling of serum cr to ≥2.5 mg/dL in less than 2 weeks with no responce to stopping diuretics and giving plasma expansion

Exclusion criteria

  • Obstructive nephropathy
  • Parenchymal renal disease (ATN, glomerular disease, interstitial nephritis)
  • Use of renal toxic medications
  • Shock
  • Uncontrolled bacterial infection
  • Uncorrected fluid losses
  • Liver disease due to factors which are also nephrotoxic (e.g. acetominophen)
  • Severe cardiovascular disease (investigators discretion)

Intervention: Patients were randomized to either 1 mg terlipressin q6h or matching placebo. If after 3 days the patients had not had a decrease in Cr of 30% the study drug was doubled to 2 mg q6h. The protocol recommended daily albumin infusions (100 g on day one and 25 g daily after that). The protocol prohibited concomitant use of vasocontrictors (dopamine, norepinephrine) prostaglandin, NSAIDs.

Primary end-point: percent of patiens with a serum Cr ≤1.5 on two measurements 48 hours apart without dialysis, death or recurrence of HRS.

Secondary end-points:

  1. Change in serum Cr from baseline to day 14
  2. incidence of treatment failure (Cr ≥ baseline after day 7, dialysis, death)
  3. Combined incidence of treatment success and partial response (Cr decreased by >50% but not ≤ 1.5) without diqalysis or recurrence of HRS
  4. Survival [Yay!] at 60 days (though they did not show the results)
  5. Transplant-free survival at 60 days (though they did not show the results)
  6. Survival at 180 days
  7. Transplant-free survival at 180 days

Results:

They randomized 112 patients from 35 centers.
More patients in the terlipressin group had a Cr > 7, though the average creatinine was 3.96 in the experimental group and 3.85 in the control group.

The Table 1 did not have p values to allow you to compare differences between the two groups.

The primary outcomes were summarized in Table 2:
The primary outcome is the first line “Treatment success at day 14” and unfortunately they “Missed it by that much” with a p value of 0.093. The next line is HRS reversal which according to the article is the traditional definition of response to therapy in prior investigations of HRS. It is interesting that if the authors had used this “traditional” end-point we would be dancing in the streets about a positive therapy but since they selected a more stringent criteria of response (under pressure from the FDA?) they have a negative trial. The power analysis they provided states they predicted a 50% response rate for terlipressin and a 5% response for the placebo. They actually found a 25% response for terlipressin and 12.5% for placebo. So one cold look at this as an underpowered study because they did not meet the effectiveness they estimated in the power analysis.

The authors then provide an intriguing figure which shows that the patients who recovered in the placebo group, all recovered very early while the recoveries in the terlipressin group occurred through the period the drug was administered.
I believe the point was to show proof of efficacy, implying that the early spontaneous recoveries in the placebo group were due to misdiagnosis or lack of serious disease while the recovery of patients in the terlipressin’s group increased with increasing duration of therapy. I find this fairly compelling.

One of the secondary outcomes was survival (Yay!). There was no difference in survival between the two groups.

Though I love investigators that have the cojones to look at survival, it is a little strange in HRS because the renal failure is secondary to another life threatening primary illness, liver failure. Even if the therapy is perfectly effective at reversing the renal failure, the long-term survival is dependent on getting a liver transplant or spontaneous recovery of the liver disease. One might argue that curing the renal failure would extend the life of the patient making a transplant more likely but since renal failure is a large component of the MELD score, curing the renal failure actually pushes patients down the list for a liver transplant. So in my mind, the lack of a survival benefit in the treatment of HRS is not nearly as damaging as it normally is.

My final conclusion is that though the study did nt reach scientific signifigance for its primary outcome it did demonstrate compelling evidence for positive biologic activity and since all of the alternative therapies have worse data I would use terlipressin if it was available. My guess though is this negative trial will mean that it will not be licensed and distributed in the U.S.