CONTENTS
- Rapid Reference 🚀
- Background: Hepatorenal physiology
- Prevention of HRS-AKI
- Clinical presentation
- Differential diagnosis
- Evaluation
- Treatment
- Podcast
- Questions & discussion
- Pitfalls
#1) criteria to suspect HRS-AKI:
- Cirrhosis with ascites.
- Oliguric AKI (<500 ml/day).
- MAP is usually low.
#2a) evaluation: 📖
- Evaluation of volume status with POCUS.
- Review recent events, medications (e.g., nephrotoxins).
- Urinalysis.
- Creatinine kinase level if rhabdomyolysis is suspected.
- Consider evaluation for sepsis (e.g., blood cultures, paracentesis, chest X-ray).
- Renal ultrasonography.
#2b) empiric support for HRS-AKI (don't delay)
- Discontinue nephrotoxins, including:(36812435)
- Antihypertensives (e.g., beta-blockers, vasodilators).
- Diuretics.
- Vasopressor: 📖
- Target MAP elevation by >15 mm from baseline (e.g., MAP >85 mm).
- Norepinephrine is usually front line in the United States.
- Albumin: 📖
- 1 gram/kg/day up to 100 grams in divided doses for 2 days, then 20-40 grams/day.
- Either 5% or 25%, depending on volume status.
- Therapeutic paracentesis for tense ascites. 📖
hepatorenal physiology: systemic vasodilation and renal vasoconstriction
- Liver failure causes systemic vasodilation due to a release of vasodilators (e.g., nitric oxide) from hepatic circulation. This causes:
- Low systemic vascular resistance (SVR)
- Low blood pressure
- Increased cardiac output
- In attempts to compensate for this systemic vasodilation, the sympathetic nervous system and the renin-angiotensin-aldosterone system are activated (releasing endogenous norepinephrine and angiotensin-II).
- Initially, these systems are able to compensate.
- Beyond a certain point, patients develop refractory systemic vasodilation. Unfortunately, endogenous norepinephrine and angiotensin-II remain successful at causing renal vasoconstriction. The ultimate result is systemic vasodilation with renal vasoconstriction, causing inadequate renal perfusion.
relationship of HRS-AKI to acute tubular necrosis (ATN)
- HRS-AKI is due to intense renal vasoconstriction, causing renal hypoperfusion. As such, it may be conceptualized as a reversible form of “pre-renal” renal failure. If hemodynamic abnormalities are reversed, HRS-AKI is expected to resolve.
- However, if HRS-AKI is left untreated, hypoperfusion may eventually lead to dysfunction of the renal tubules (acute tubular necrosis), with intrinsic renal failure. Thus, HRS-AKI may eventually transition to a state of acute tubular necrosis (ATN).(31723234)
avoid nephrotoxins
- Whenever possible, nephrotoxins should be avoided in patients with advanced cirrhosis (especially NSAIDs, ACE inhibitors, and angiotensin receptor blockers).
- List of nephrotoxins here: 📖
albumin administration
- (1) For large volume paracentesis (>~5 liters), administration of ~8 grams albumin per liter of fluid removed may reduce the risk of hepatorenal syndrome.(3360270)
- (2) In spontaneous bacterial peritonitis, albumin has been proven to dramatically reduce the risk of hepatorenal syndrome (more on this here).
Patients will present at various stages in the disease process. For example, some patients may develop HRS-AKI while in the hospital, whereas others may present to the hospital with advanced disease. Diagnosis is generally made on the basis of recognizing some constellation of three factors: at-risk patients, precipitating factors, and kidney injury.
#1) substrate: at-risk patients
- (1) HRS-AKI usually occurs in the context of advanced cirrhosis with ascites (although it can occur in acute liver failure or alcoholic hepatitis).
- (2) The greatest risk is among patients with chronically borderline perfusion. Clinically, this may be revealed by:
- Chronic hypotension.
- Chronic hyponatremia.
#2) precipitating factor
- Any hemodynamic stress, such as:
- Infection (e.g., spontaneous bacterial peritonitis).
- Volume depletion (e.g., large volume paracentesis, hemorrhage, over-diuresis).
- Volume overload (e.g., portopulmonary hypertension with systemic congestion).
- Vasodilatory medications (e.g., ACE inhibitors).
- Increased intra-abdominal pressure due to tense ascites.
- Surgery.
- Deterioration in liver function (e.g., acute-on-chronic liver failure).
#3) kidney injury
- This presents in a similar fashion to any other form of renal failure due to malperfusion, typically:
- (a) Oliguria (e.g., daily urine output below ~500 ml).
- (b) Bland urine sediment (without evidence of glomerulonephritis or tubular necrosis).
- Elevated creatinine. When interpreting creatinine in patients with cirrhosis, bear in mind that these patients often have low muscle mass and enhanced renal creatinine secretion, leading to artificially low creatinine values. Therefore:
- (#1) The creatinine level tends to overestimate renal function. For example, a patient with cirrhosis and a creatinine of 1.0 mg/dL may have substantial renal dysfunction.
- (#2) Small changes in creatinine may be significant. For example, if the creatinine rises from a baseline of 0.3 mg/dL to 1 mg/dL, that may reflect a major reduction in renal function (and meet criteria for acute kidney injury).
HRS-AKI only accounts for ~20% of cases of acute kidney injury among patients with cirrhosis.(32832400) Other common causes of AKI in this patient population are listed below (a full differential diagnosis of AKI is here: 📖)
common causes of AKI in the context of cirrhosis:
- HRS-AKI.
- Shock/hypoperfusion of any etiology:
- Septic shock.
- Hemorrhagic shock.
- Hypovolemia:
- Over-diuresis.
- Poor oral intake.
- Volume overload (i.e., congestive nephropathy).
- This may be more likely in patients with pulmonary hypertension.(35373127)
- Abdominal compartment syndrome (due to large-volume, tense ascites).
- Intrinsic renal failure:
- Nephrotoxic medications.
- Glomerulonephritis (e.g., may associate with chronic HBV or HCV).
- AIN (acute interstitial nephritis).
- ATN (acute tubular necrosis).
- Postrenal failure (e.g., Foley catheter dysfunction).
evaluation usually involves:
- Renal ultrasonography.
- Review of medications for nephrotoxins.
- Urinalysis.
- Evaluation of the hemodynamic status:
- History is important (e.g., changes in diuretic prescription, lactulose use, oral fluid intake).
- Bedside evaluation with echocardiography.
- Evaluation for infection (e.g., paracentesis, urinalysis, chest X-ray).
POCUS evaluation of hemodynamic status
- Findings may vary considerably, with specific implications for therapy.(31723234) For example:
- (1) A small and highly collapsible IVC may support a diagnosis of hypovolemia.
- (2) A small IVC without respirophasic variation might suggest the presence of intra-abdominal hypertension, especially if combined with tense and large-volume ascites. Such patients may benefit from therapeutic paracentesis to reduce their intra-abdominal pressure and thereby improve renal perfusion.
- (3) Congestive nephropathy may be supported by findings of systemic congestion (e.g., dilation of the IVC).
urine electrolytes aren't well supported by evidence
- Urine sodium and urinary fractional excretion of sodium (FeNa) are no longer part of the diagnostic criteria for HRS-AKI, due to inability to distinguish HRS-AKI from acute tubular necrosis.(32928750)
- Fractional excretion of urea (FeUrea) might be more useful. It can be calculated using MDCalc. A recent study found the following values:(29315697)
- HRS-AKI: Median FeUrea ~17 (interquartile range ~5-30).
- Prerenal azotemia: Median FeUrea ~26 (interquartile range ~15-48).
- Acute Tubular Necrosis: Median FeUrea ~44 (interquartile range ~33-59).
- Values of FeUrea overlap considerably, so this test should be interpreted with caution. Furthermore, this study requires replication.
- Overall, currently there is no solid evidence-based medicine justification to use urine electrolytes to diagnose HRS-AKI. Urine electrolytes may be more likely to delay therapy and to mislead, rather than to provide useful information.
official diagnostic criteria for HRS-AKI
- Diagnostic criteria technically require all of the following:
- (1) Acute kidney injury, defined as:
- An increase in creatinine of >0.3 mg/dL, within 48 hours.
- -or-
- An increase in creatinine to >1.5 times baseline, within a week.
- (2) No response to diuretic withdrawal and a two-day fluid challenge with 1 gram/kg/day of 20-25% albumin to a maximum of 100 grams/day.
- (3) Cirrhosis with ascites.
- (4) Absence of shock.
- (5) No current or recent use of nephrotoxic drugs.
- (6) No signs of structural kidney injury:
- Absence of proteinuria (>500 mg/day).
- Absence of hematuria (>50 RBCs per high-power field), although in the presence of a Foley catheter this may merely reflect minor Foley catheter trauma.
- Normal findings on renal ultrasound.
problems with the traditional approach to diagnosing HRS-AKI
- A key element of the traditional diagnosis of HRS-AKI is to first provide the patient with a volume challenge of albumin for two days. If the patient responds to volume loading, then they are diagnosed with prerenal kidney failure. Alternatively, if the patient fails to respond to volume loading, then they are diagnosed with HRS-AKI. This strategy suffers from several major problems:
- (#1) Delaying treatment for two days may impair outcomes. Treatment of HRS-AKI is more likely to be successful if initiated earlier, when the creatinine is lower.(32928750)
- (#2) Occasional patients with cirrhosis may develop volume overload with elevated filling pressures, leading to congestive nephropathy. Administration of albumin to such patients is likely to exacerbate their renal dysfunction.
- (#3) Hepatorenal physiology (i.e., systemic vasodilation with inadequate renal perfusion) may often coexist with other renal insults (e.g., hypovolemia or acute tubular necrosis). Therefore, a binary, dichotomous attempt to parse these out as separate conditions is fundamentally flawed among more complex patients.
- (#4) The volume of fluid used to resuscitate the patient is arbitrary and fixed (1 gram/kg/day). For some patients this may be inadequate, whereas for others it may be an excessive volume of fluid.
- The traditional approach to HRS-AKI diagnosis utilizing an albumin challenge could be appropriate for patients with mild renal dysfunction who are not critically ill (e.g., patients on a hospital ward). However, for patients who have been admitted to the ICU due to critical organ failure(s), a more aggressive strategy may be needed.
Below is an accelerated approach to hepatorenal syndrome, which may be more appropriate in the ICU. Some key elements of this strategy:
- Volume status is determined clinically (based on history, examination, and POCUS). Rather than giving a fixed volume of albumin to every patient, fluid management may be individualized based on clinical assessment (e.g., patients with congestive nephropathy may benefit from diuresis, whereas patients with marked hypovolemia may benefit from more aggressive volume resuscitation).
- For patients who appear to have HRS-AKI, vasoconstrictor therapy can be started early (well before the traditional delay of >48 hours).
When in doubt, it's probably better to err on the side of supporting renal perfusion with vasopressors and albumin:
- If the patient has HRS-AKI, then early therapy will be beneficial.
- If you're wrong and the patient is hypovolemic, albumin and vasopressors will still probably help them.
- Hepatorenal syndrome is a sign of overall poor prognosis.
- Patients who may be transplantation candidates should be discussed with a transplant service or regional transplant center.
indication for vasopressors?
- European guidelines recommend reserving vasoconstrictors for patients with HRS-AKI Stage IB (serum creatinine >1.5 g/dL) since more mild forms are likely to resolve with fluid expansion alone.(29653741) However, for patients who are already admitted to the ICU, there may be little reason to delay vasopressor initiation.
choice of vasopressor
terlipressin
- Terlipressin is a selective agonist of V1 vasopressin receptors. It is often recommended as the front-line vasopressor for HRS-AKI. However, there isn't clear evidence that terlipressin is actually superior to other vasoconstrictors.(28953318)
- Terlipressin is currently unavailable at many centers in the United States.
- Terlipressin has been associated with pulmonary edema, so it may be contraindicated among patients with evidence of intravascular volume overload (e.g., anasarca, jugular venous distension, hypoxemia, pulmonary congestion on chest X-ray, or elevated right ventricular systolic pressure on echocardiography).(36812435)
norepinephrine is a front-line agent in the United States
- RCTs have generally found norepinephrine to be equally as effective as terlipressin, possibly with a superior safety profile.(25203311) However, one study investigating acute-on-chronic liver failure did find terlipressin to be superior.(30076614)
- One advantage of norepinephrine is that it can be administered via peripheral line at low to moderate doses. Additionally, norepinephrine is easier to titrate rapidly over a broad dose range, in order to promptly achieve blood pressure targets.
vasopressin
- Vasopressin might be expected to have a similar efficacy compared to terlipressin, since it also hits the V1 vasopressin receptor. However, this has not been investigated.
- Studies in septic shock have suggested that vasopressin may have a slight advantage over norepinephrine in the preservation of renal function during vasodilatory shock states.
- Drawbacks of vasopressin:
- (1) It may exacerbate hyponatremia, by promoting renal retention of free water.
- (2) It shouldn't be infused peripherally.
- (3) Lack of evidentiary basis in HRS-AKI.
{midodrine plus octreotide}
- This combination has been found to be substantially less effective than terlipressin or norepinephrine.(25644760) It doesn't usually doesn't play a role in the initial therapy of patients who have been admitted to the ICU.
- Midodrine is started at 10 mg PO q8hrs and aggressively uptitrated to increase the MAP by >10-15 mm (this strategy will not work if midodrine isn't uptitrated adequately). Octreotide may be given at a dose of 200 micrograms subcutaneously q8hr.
- 🎶 Please note that octreotide is unnecessary for patients who are being treated with norepinephrine or vasopressin. The only evidence-based role of octreotide is as part of a cocktail combined with midodrine.(12830007)
hemodynamic goals
- Achieving an increased MAP has been associated with improvements in renal function.(32928750) This is probably more important than the choice of medication used (midodrine, vasopressin, or norepinephrine).
- A typical target might be a MAP rise of ~15 mm, and/or a MAP >85 mm.(31723234)
- (Note that if the baseline MAP is >85 mm, the patient probably doesn't actually have HRS-AKI.)
duration of IV vasopressors & transition to oral midodrine
- The optimal duration of IV vasopressor therapy is unknown, with clinical studies varying between 5-14 days.(31723234) Vasopressors should perhaps be continued until the renal function has improved and stabilized (e.g., returned to baseline or reached a plateau value).
- If there is difficulty weaning off vasopressors (e.g., with deterioration in blood pressure or renal function), then transitioning from IV vasopressor infusion to oral midodrine may be considered.
- One RCT among outpatients with cirrhosis and refractory ascites found that chronic therapy with midodrine improved control of ascites and reduced mortality.(21749847) Although this is a small study, it does support the concept of using chronic midodrine therapy to support patients with cirrhosis and chronic systemic vasodilation.
- The MIDAS trial did not support the use of oral midodrine in a general population of ICU patients being weaned off vasopressors.(32885276) However, midodrine may be more beneficial among patients with cirrhosis and chronic vasodilation.
rationales for use of albumin
- Combining albumin with vasoconstrictors is evidence-based as front-line therapy for HRS-AKI.
- How albumin works is unclear, with possible mechanisms including the following:
- Volume expansion (however, this is not the sole mechanism of action, since albumin seems to be more effective than other fluids).
- Albumin may adsorb some circulating toxins.
- Albumin may promote the function of the endothelial glycocalyx.
dosing of albumin
- On day #1-2, 1 gram/kg per day (up to a maximum of 100 grams) is often used.
- It may be beneficial to give this in divided doses (e.g., 25 grams Q6hr).(31723234)
- Subsequently, the dose may be decreased to 20-40 grams daily.
- Studies have generally utilized 5% albumin. However, for patients who appear euvolemic or hypervolemic, 25% albumin is probably better.
diuretics
- Diuretics should generally be held for patients in hepatorenal syndrome.(29653741)
- Rare patients may have a combination of hepatorenal physiology (systemic vasodilation) plus congestive nephropathy (elevated central venous pressure (CVP)). In this situation, the renal perfusion pressure (equal to MAP-CVP) is severely reduced, promoting renal failure. If there is unequivocal evidence of systemic congestion on echocardiography, then a “squeeze and diurese” strategy may be employed:
- i) Vasoconstrictors are utilized to increase the MAP.
- ii) Diuretics are simultaneously utilized to relieve systemic congestion.
- Among patients with tense ascites, abdominal hypertension may be one factor which is contributing to renal dysfunction (more on abdominal compartment syndrome: 📖).
- Therapeutic paracentesis is a rational therapy if there is concern for intra-abdominal hypertension. One study found an increase in renal function following therapeutic paracentesis plus albumin administration.(18197961) However, partial fluid removal (rather than large volume paracentesis) might be preferable, since large volume paracentesis can actually precipitate HRS-AKI.(36812435)
- Relative adrenal insufficiency is present in about a third of patients with decompensated cirrhosis and ascites (this is termed “hepatoadrenal syndrome”). This may contribute to vasodilation and renal hypoperfusion.(32928750)
- Current evidence doesn't support the use of steroid to treat hepatorenal syndrome. However, if there are considerations for potentially using steroid for other indications (e.g., septic shock or alcoholic hepatitis), the presence of hepatorenal syndrome might serve as a weak suggestion in favor of using steroid.
dialysis may be beneficial in some situations
- Bridge to liver transplantation or recovery from a reversible kidney insult.
- Kidney dysfunction is disproportionately severe, compared to the degree of hepatic dysfunction.
dialysis may be nonbeneficial in other situations:
- If the patient isn't a transplant candidate and there is no other etiology of renal failure (i.e., the patient solely has hepatorenal syndrome), dialysis is unlikely to affect the overall prognosis. Some authors do not recommend initiation of dialysis for patients with hepatorenal syndrome who are not candidates for liver transplantation.(32928750)
- Patients with hepatorenal syndrome often have relative hypotension and endothelial dysfunction (causing difficulty retaining fluid within their vasculature). Intermittent hemodialysis may be difficult or impossible in this context, as patients may be unable to tolerate the hypotension and fluid shifts involved. Continuous renal replacement therapy (CRRT) is better tolerated, but this requires ongoing ICU admission, which isn't conducive to a high quality of life.
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- Failure to consider hepatorenal syndrome in a complex patient with many active problems (e.g., spontaneous bacterial peritonitis, renal failure, and mild encephalopathy).
- Delaying therapy until a sophisticated workup is completed, by which point the renal injury has progressed.
- Administering NSAIDs, which should generally be avoided in ICU patients, but which are especially detrimental to patients with cirrhosis.
Guide to emoji hyperlinks
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References
- 03360270 Ginès P, Titó L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology. 1988 Jun;94(6):1493-502. doi: 10.1016/0016-5085(88)90691-9 [PubMed]
- 12830007 Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology. 2003 Jul;38(1):238-43. doi: 10.1053/jhep.2003.50276 [PubMed]
- 18197961 Umgelter A, Reindl W, Wagner KS, et al. Effects of plasma expansion with albumin and paracentesis on haemodynamics and kidney function in critically ill cirrhotic patients with tense ascites and hepatorenal syndrome: a prospective uncontrolled trial. Crit Care. 2008;12(1):R4. doi: 10.1186/cc6765 [PubMed]
- 21749847 Singh V, Dhungana SP, Singh B, et al. Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. J Hepatol. 2012 Feb;56(2):348-54. doi: 10.1016/j.jhep.2011.04.027 [PubMed]
- 25644760 Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology. 2015 Aug;62(2):567-74. doi: 10.1002/hep.27709 [PubMed]
- 29315697 Patidar KR, Kang L, Bajaj JS, Carl D, Sanyal AJ. Fractional excretion of urea: A simple tool for the differential diagnosis of acute kidney injury in cirrhosis. Hepatology. 2018 Jul;68(1):224-233. doi: 10.1002/hep.29772 [PubMed]
- 29653741 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69(2):406-460. doi: 10.1016/j.jhep.2018.03.024 [PubMed]
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- 32846202 Ojeda-Yuren AS, Cerda-Reyes E, Herrero-Maceda MR, Castro-Narro G, Piano S. An Integrated Review of the Hepatorenal Syndrome. Ann Hepatol. 2020 Aug 23;22:100236. doi: 10.1016/j.aohep.2020.07.008 [PubMed]
- 32885276 Santer P, Anstey MH, Patrocínio MD, et al.; MIDAS Study Group. Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial. Intensive Care Med. 2020 Oct;46(10):1884-1893. doi: 10.1007/s00134-020-06216-x [PubMed]
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- 35373127 Velez JCQ. Hepatorenal Syndrome Type 1: From Diagnosis Ascertainment to Goal-Oriented Pharmacologic Therapy. Kidney360. 2021 Dec 3;3(2):382-395. doi: 10.34067/KID.0006722021 [PubMed]
- 36812435 Nadim MK, Garcia-Tsao G. Acute Kidney Injury in Patients with Cirrhosis. N Engl J Med. 2023 Feb 23;388(8):733-745. doi: 10.1056/NEJMra2215289 [PubMed]
Image credit: MAP versus renal perfusion pressure curve from Roey GV and Moore K et al.
PMID: 35487604 DOI: 10.1016/j.cld.2022.01.002