KIDNEYcon returns for its 3^rd year in 2018, hosted by UAMS in Little Rock, Arkansas. This year, morning workshops covered a range of options including interventional nephrology, ultrasound training, kidney biopsy, fluid/electrolyte/acid-base didactics, kidney pathology, communication skills, and even a workshop focused on becoming a physician scientist.

The afternoon on Day 2 focused on 2 main themes: AKI in the context of liver disease and nephrolithiasis. This post will focus on the sessions pertaining to liver disease and will cover the pathophysiology beyond the underfill hypothesis, abdominal pressures, volume assessment, and when/how to use vasoconstrictor therapy in these challenging clinical scenarios. The next piece on the stone session will be posted separately.

Pathophysiology of Hepatorenal Syndrome (HRS): Beyond Peripheral Vasodilation (Luis Juncos, MD, UAMS)

One of the most challenging concepts of HRS is the pathophysiology. Before embarking on discussions about treatment, an attempt at understanding how/why this occurs is worthwhile. Its negative effects on morbidity, mortality, and transplant outcomes are not in question here; rather, the focus is on the hemodynamic and vascular changes related to this all too common problem.

Point #1: The reversibility of HRS may not be as prompt or as reliable as early literature reported. There are direct renal effects of the systemic arterial vasodilation that go beyond renal vasoconstriction that are not well understood. The classic angiographic image of a hepatorenal kidney compared to control shows the intense vasoconstriction and sodium avidity of the disease. Although we don’t fully understand the mechanism, it seems that this prolonged ischemia may lead to delayed or incomplete recovery even after liver transplantation or recovery.

The Animal Model: Using rat models of liver disease (via chronic bile duct ligation), they demonstrated that vascular perfusion in rat kidneys was indeed decreased in HRS (no surprise here). Using microperfusion, they also showed that there was significant endothelial dysfunction within renal arterioles. This was demonstrated by increased sensitivity to angiotensin and norepinephrine, leading to profound vasoconstriction. There were also effects on tubuloglomerular feedback and even constriction of mesangial cells within the kidney parenchyma. So yes, there is hemodynamic underfill, but also structural changes in the kidney as well

Treatment Options in Animal Models: Using the hypothesis of the oxidative stress pathways, they showed that Vitamin E reversed these vascular constrictive properties in animal models using modeled CT imaging. Using in vivo laser Doppler measurement, they also showed improved measurements of renal blood flow in the Vitamin E treated rats. In humans, this was trialed in 12 patients with HRS in 1999 using N-acetylcysteine (NAC). Using high doses of intravenous NAC, the authors here showed improved kidney function and urine output in this small cohort. However, this is still not widely adopted, and large-scale data is lacking.

THE TAKEAWAY: The kidney is not a hemodynamic bystander in this phenomenon and is actually a victim of end-organ injury. While the oxidative stress pathway showed some promise, the heterogeneity of these patients and the multiple pathways of kidney injury make this a complicated disease. We have a while to go to identify human therapeutic targets in HRS.

Abdominal Perfusion Pressure AKI (Michael Connor, Jr, MD, Emory)

Prefaced from the get-go: this talk is more hypothesis-generating than guideline-based. There are numerous guidelines for diagnosing HRS, infusing albumin, etc. No such guideline on measuring bladder pressures exist quite yet.

DEFINITIONS: Intra-abdominal pressure (IAP) is the steady state pressure within the abdominal cavity. This is generated by our solid/hollow organs, space occupying lesions like fluid or tumors, and abdominal wall compliance. A normal IAP is 0-4 mm Hg. A sustained or pathologic IAP > 12 mm Hg is called intra-abdominal hypertension, and the more severe levels where IAP > 20 mm Hg are often termed abdominal compartment syndrome.

PERFUSION IS THE PROBLEM: Abdominal perfusion pressure (APP) is the mean arterial pressure (MAP) minus IAP, with the goal of > 60 mm Hg. This can be thought of similarly to cerebral perfusion pressure. Drops in the MAP or elevations in IAP can lead to problems with abdominal perfusion. Unfortunately, our exam is relatively insensitive in picking this up. A tense, rigid abdomen in the right clinical scenario is pretty sensitive in the right clinical scenario. However, a soft abdomen can still have poor perfusion. The gold standard is direct measurement of IAP via a 3-way stopcock during paracentesis. However, in most settings, the bladder pressure correlates well with direct IAP measurement. Continuous measurements can be done via pressure transducers in Foley catheter, but can also be done intermittently. In addition to abdominal catastrophes and tense edema, a MAJOR risk factor for this is volume overload.

Elevated IAP leads to effects on cardiac output, venous return, lung tidal volumes, and other systemic effects. What are the direct effects on kidney function? Obviously, there is impaired kidney perfusion – this is multifactorial due to nephroedema, increased interstitial pressure, increased venous pressure, raised tubular pressure, and ultimately kidney compression. This has been demonstrated in animal models by simple installation of saline into the peritoneal cavity of mice.

Treatment options include two strategies, either lowering abdominal pressure or increasing mean arterial pressure. The first can be accomplished by large volume paracentesis, surgical decompression, lowering PEEP, but also minimizing volume expansion! Higher MAP targets can be targeted by treating infections and vasopressors.

THE TAKEAWAY: Elevations in IAP are seen frequently in ICU patients, so don’t be afraid to check bladder pressures. Volume overload is another major risk factor for this development. More research on this topic is absolutely needed – a Chinese group has even looked at the use of rhubarb enemas in decreasing IAP!

Vasoconstrictor Therapy in Hepatorenal AKI: When to Use it and How? (Juan Carlos Velez, MD, Ochsner Clinic)

HRS is by definition a diagnosis of exclusion. This is easier said than done but let’s theoretically pretend that you as the clinician feel very confidently that you have excluded other etiologies. When should we ultimately pull the trigger and use vasoconstrictor therapies in HRS? Can we identify patients that have “functional” AKI and treat them with vasoconstrictors to prevent progression to ischemia and overt kidney injury?

Data on terlipressin (V1a agonist) show that 3-month survival without transplant with HRS is abysmal at 4%. Therapy with terlipressin improved mortality to 41%. Looking at midodrine/octreotide vs renally dosed dopamine was very impressive, but this prospective data enrolled only 13 patients. An Italian trial showed that terlipressin was superior to octreotide/midodrine. Even norepinephrine has some decent data and is considered comparable to terlipressin. A meta-analysis of all HRS vasoconstrictor trials showed that as MAP increases, kidney function also improved. Importantly, not all patients that responded had low starting MAP, so this can still be considered in “normotensive cirrhotics.” The CONFIRM Trial in the US is looking at terlipressin therapy and is expected to complete enrollment by 2020.

THE TAKEAWAY: In the US, the best option we currently have for HRS is octreotide/midodrine. If there is no improvement, consider switching to IV norepinephrine with the goal to raise MAP by 15 mm Hg. If there is no response within 3 days, stop therapy and throw in the towel. Hopefully in a few years, we will have terlipressin data and approval in the US which has consistently shown to be better than our current midodrine/octreotide cocktail

More to come on stones in the next post available here. Thanks to all the #KIDNEYcon speakers!

– Post prepared by Timothy Yau, AJKD Social Media Editor. Follow him @Maximal_Change.