Hepatorenal syndrome (HRS) represents a severe complication of advanced liver cirrhosis, characterized by extreme circulatory dysfunction and associated with significant morbidity and mortality. The diagnostic criteria for HRS have recently evolved, moving away from a fixed serum creatinine threshold to incorporate changes in serum creatinine as per the acute kidney injury (AKI) criteria. This shift, alongside emerging data on urinary biomarkers, particularly neutrophil gelatinase-associated lipocalin (NGAL), is refining Hrs Diagnosis and clinical management. Current treatment standards revolve around terlipressin and albumin administration, with continuous terlipressin infusion showing improved tolerability. However, treatment efficacy remains limited to 40%-50% of patients, highlighting the urgent need for innovative therapeutic strategies. Liver transplantation remains the definitive curative option for eligible patients. Preventive measures, such as albumin volume expansion in spontaneous bacterial peritonitis and post-large volume paracentesis, and antibiotic prophylaxis in high-risk cirrhotic patients, are crucial in reducing HRS incidence. This review examines the latest advancements in HRS diagnosis, treatment, and prevention, offering insights into this critical condition.
PATHOPHYSIOLOGY OF HRS
HRS pathogenesis is rooted in profound circulatory dysfunction arising from advanced liver cirrhosis. The cirrhotic liver’s hepatocytes and stellate cells produce an array of local vasodilators, including nitric oxide and cannabinoids, predominantly impacting the splanchnic circulation. This splanchnic arterial vasodilation leads to a reduction in mean arterial pressure (MAP), triggering compensatory mechanisms like sympathetic nervous system activation. Early compensation involves elevated circulating noradrenaline and increased cardiac output to stabilize MAP[1].
As cirrhosis progresses, splanchnic vasodilation intensifies, activating other vasoconstrictor systems such as the renin-angiotensin-aldosterone system and vasopressin release[1]. Aldosterone promotes renal sodium and water retention, contributing to ascites development, while vasopressin enhances free water retention, potentially leading to hyponatremia. Notably, the splanchnic vasculature becomes increasingly resistant to these vasoconstrictor systems, which paradoxically act effectively on other vascular beds, including femoral, brachial, cerebral, and renal arteries[1,2]. This differential vasoconstriction is evidenced by a progressive increase in mean renal artery resistive index across stages of cirrhosis, from no ascites to ascites, refractory ascites, and ultimately HRS[3,4].
Therefore, HRS is a functional renal disorder characterized by marked renal artery vasoconstriction. This vasoconstriction is a consequence of overactivated systemic vasoconstrictor systems attempting to compensate for systemic vasodilation initiated by splanchnic vasodilation. HRS invariably occurs in the context of advanced circulatory dysfunction and is almost always associated with ascites and frequently with hyponatremia[1].
Infection, particularly spontaneous bacterial peritonitis (SBP), can precipitate HRS due to sepsis-induced worsening of circulatory dysfunction. Albumin volume expansion has proven effective in preventing HRS development in SBP patients[5]. Similarly, HRS can develop post-large volume paracentesis (LVP) due to circulatory disturbance, a complication effectively mitigated by albumin replacement following LVP[6].
DIAGNOSTIC CRITERIA FOR HRS BASED ON AKI DEFINITION
Traditionally, acute renal failure in cirrhosis was defined by a ≥ 50% increase in serum creatinine (sCr) from baseline, reaching a final level above 1.5 mg/dL (133 μmol/L). HRS type-1 was classically defined by a doubling of sCr levels to over 2.5 mg/dL (220 μmol/L) within two weeks. However, serum creatinine is an imperfect marker of renal function in cirrhotic patients due to factors such as reduced creatinine production from muscle wasting, increased tubular creatinine secretion, dilution effects from increased volume of distribution, and bilirubin interference with sCr assays.
Recognizing these limitations, the International Club of Ascites (ICA) adopted the AKI criteria, initially developed for general critically ill patients. AKI is now defined as an increase in sCr by at least 0.3 mg/dL (26 μmol/L) within 48 hours, or a ≥ 50% increase from baseline within 7 days[7].
The ICA-AKI based HRS diagnosis criteria include[7]:
- Presence of cirrhosis and ascites.
- AKI diagnosis according to ICA-AKI criteria.
- No improvement after at least 48 hours of diuretic withdrawal and plasma volume expansion with albumin (1 g/kg body weight).
- Absence of shock.
- No current or recent nephrotoxic drug exposure (NSAIDs, aminoglycosides, iodinated contrast, etc.).
- Absence of macroscopic structural kidney injury, indicated by:
- Proteinuria < 500 mg/day.
- Microhematuria < 50 red blood cells per high power field.
- Normal renal ultrasound findings.
A key change with the AKI-based HRS diagnosis is the elimination of a rigid, high sCr cut-off (2.5 mg/dL or 220 μmol/L) for initiating pharmacological treatment. This allows for earlier intervention, potentially improving treatment efficacy. However, these clinical criteria alone cannot reliably differentiate HRS from parenchymal renal diseases, which is critical as vasoconstrictors are ineffective and potentially harmful in parenchymal disease. Consequently, there is significant interest in urinary biomarkers to enhance the differential diagnosis of HRS.
ROLE OF URINARY BIOMARKERS IN AKI AND HRS DIAGNOSIS
Numerous urinary biomarkers have been investigated in AKI and liver cirrhosis, including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18, liver-type fatty acid binding protein (L-FABP), kidney injury molecule-1, toll-like receptor 4, π-glutathione S-transferase, and α-glutathione S-transferase[8]. Among these, urinary NGAL currently shows the most promise in refining HRS diagnosis.
NGAL is particularly useful in identifying acute tubular necrosis (ATN), a structural kidney injury, and distinguishing it from HRS. NGAL levels are significantly elevated in ATN compared to other causes of AKI, including pre-renal azotemia and HRS. Studies have shown urinary NGAL levels in ATN to be around 417 μg/L, while levels are substantially lower in pre-renal azotemia (30 μg/L), chronic kidney disease (82 μg/L), and HRS (76 μg/L, P < 0.001)[9,10].
Integrating urinary NGAL into the HRS diagnosis algorithm can help rule out structural kidney injury, specifically ATN. This is crucial because patients with ATN will not benefit from vasoconstrictor therapy, and such treatment could even exacerbate renal dysfunction and lead to serious side effects[11]. Therefore, NGAL aids in more precise patient stratification for targeted therapy.
Alt text: Diagnostic algorithm for hepatorenal syndrome incorporating urinary NGAL biomarker to differentiate acute tubular necrosis and guide treatment decisions.
CURRENT STANDARD TREATMENT FOR HRS
Once AKI patients with cirrhosis have undergone volume expansion with albumin (1 g/kg) for 48 hours without improvement and meet HRS diagnosis criteria, terlipressin treatment is recommended. Albumin infusion should continue at 20-40 g daily. Treatment response should be regularly assessed, and terlipressin titrated up to a maximum of 12 mg/day, used for a maximum of 14 days, and discontinued if ineffective[7].
Treatment response is defined as a ≥ 25% reduction in sCr from baseline levels (pre-terlipressin initiation)[7]. Response rates with terlipressin and albumin are approximately 40%-50%, with a recurrence rate of 30%. Liver transplantation (LT) is the definitive treatment for HRS, addressing the underlying liver dysfunction and circulatory abnormalities. LT should be considered for all eligible patients. Terlipressin and albumin are considered a bridge to LT, not a definitive solution, given the high recurrence rate and persistent advanced circulatory dysfunction that predisposes patients to further decompensations[12]. This rationale supports HRS patient prioritization for LT in some centers.
Two randomized controlled trials have demonstrated superior HRS reversal rates with terlipressin plus albumin compared to albumin alone. Martín-Llahí et al.[13] reported significantly higher renal function improvement in the terlipressin/albumin group (43.5% vs 8.7%, P = 0.017). Sanyal et al.[14] also showed increased HRS reversal with terlipressin/albumin (33.9% vs 12.5%, P = 0.008). However, neither study showed significant differences in 3-month or 6-month survival. A more recent large randomized trial showed a trend towards higher HRS reversal with terlipressin (23.7% vs 15.2%, P = 0.13), although not statistically significant, possibly due to a substantial proportion of patients receiving less than three days of treatment, potentially impacting efficacy. However, stratified analyses indicated that any degree of sCr reduction, even without complete reversal, positively impacts survival[15].
Traditionally, terlipressin has been administered as boluses (0.5-1.0 mg every 4-6 hours). Recent evidence suggests that continuous terlipressin infusion is equally effective and better tolerated, with fewer side effects (35.29% vs 62.16%, P < 0.05) and lower daily doses (2.94 ± 1.49 mg/day vs 3.51 ± 1.77 mg/day, P < 0.05)[16].
Current recommendations favor continuous terlipressin infusion at 2 mg/day (in 250 mL Dextrose 5%) alongside albumin (20-40 g/day). Response should be assessed every 48 hours, with stepwise dose increases (2 mg/day increments) if no response is observed. Close monitoring for ischemic side effects (acral parts, cardiac events, bowel ischemia), hyponatremia, and arrhythmias is crucial during terlipressin therapy.
PREDICTORS OF RESPONSE TO TERLIPRESSIN AND ALBUMIN
Limited studies have investigated predictors of response to terlipressin in HRS. These studies indicate a strong correlation between treatment effectiveness and improvement in systemic hemodynamics. Patients failing to achieve a ≥ 5 mmHg increase in MAP by day 3 of terlipressin treatment exhibit lower response rates. Treatment efficacy also correlates with the severity of liver dysfunction. Patients with both failure to increase MAP at day 3 and baseline bilirubin levels ≥ 171 μmol/L (10 mg/dL) had a particularly poor response rate (9%)[17]. Another study suggested that lower baseline creatinine levels predict HRS reversal, implying that earlier intervention may be more effective[18].
A retrospective study found that patients with systemic inflammatory response syndrome (SIRS) had significantly higher terlipressin response rates (42.9% vs 6.7%, P = 0.018), while terlipressin showed no superiority over placebo in patients without SIRS (15.9% vs 18.8%, P = NS)[19]. A recent abstract linked non-response to higher urinary NGAL levels (728.8 μg/L vs 182.9 μg/L, P = 0.02), possibly reflecting underlying acute tubular necrosis[20].
In summary, predictors of positive response to terlipressin include: lower baseline creatinine and bilirubin levels, increase in blood pressure following treatment initiation, presence of SIRS, and lower urinary NGAL levels. These markers can aid in identifying patients more likely to benefit from standard therapy and those who may require alternative strategies or expedited LT consideration.
ALTERNATIVE TREATMENT OPTIONS FOR HRS
Liver Transplantation (LT)
For HRS type-1 patients without LT contraindications, LT evaluation and listing are paramount as LT is the only definitive cure. LT corrects both liver dysfunction and portal hypertension. HRS patients have poorer survival than other cirrhotic patients with similar MELD scores, indicating HRS as an independent poor prognostic factor[21,22]. Furthermore, early structural renal tubular injury in HRS-1 and prolonged waiting times for LT increase the risk of persistent renal dysfunction post-LT or even the need for renal transplantation[23]. Experts recommend prioritizing HRS patients by using pre-treatment creatinine levels or considering pharmacological HRS treatment as hemodialysis when calculating MELD scores[24]. However, universal consensus on HRS patient prioritization for LT is lacking, with varying practices across transplant centers due to organ scarcity and allocation complexities. Patients with recurrent HRS-1 episodes are at high risk of refractory HRS, waitlist dropout, and poor renal recovery post-LT, thus potentially benefiting most from early transplantation.
Midodrine and Octreotide
Midodrine and octreotide (MID/OCT) combined with albumin are used when terlipressin is unavailable. However, a randomized trial showed significantly lower response rates with MID/OCT compared to terlipressin (4.8% vs 55.6%, P < 0.001)[25], indicating MID/OCT is not an effective HRS treatment.
Noradrenaline
A randomized study comparing noradrenaline to terlipressin demonstrated similar HRS reversal rates (43.4% vs 39.1%) and 15-day survival (39.1% vs 47.8%, P = 0.461)[26]. A meta-analysis of four studies (152 patients) suggested noradrenaline is as effective as terlipressin for HRS reversal when combined with albumin[27]. Noradrenaline is a viable HRS therapy, although its use typically requires intensive care unit monitoring.
Dopamine
Low-dose dopamine increases renal blood flow but has not shown benefit on glomerular filtration rate or HRS outcomes. Studies have not demonstrated creatinine reduction with dopamine in HRS[28,29], and it is not considered appropriate for HRS treatment.
Transjugular Intrahepatic Portosystemic Shunt (TIPS)
TIPS is generally contraindicated in HRS type-1 due to advanced liver dysfunction. Limited small trials suggest TIPS may improve renal function and reduce vasoconstrictor system activity (renin, aldosterone, noradrenaline levels)[30,31]. However, evidence is insufficient to recommend TIPS for routine HRS management.
Renal and Liver Replacement Therapy
Hemodialysis is used as a bridge to LT in patients with HRS unresponsive to medical treatment, also potentially improving MELD scores for transplant prioritization. Molecular adsorbent recirculating system (MARS) liver support has been explored in vasoconstrictor-unresponsive patients with advanced liver dysfunction unsuitable for TIPS. One trial showed greater creatinine and bilirubin reduction with MARS versus continuous hemodialysis[32], while another found no significant hemodynamic or glomerular filtration rate changes with MARS[33]. These therapies are generally reserved for LT candidates, and their use in patients without LT options is controversial.
Serelaxin
Serelaxin, a recombinant human relaxin-2, improves renal perfusion in healthy individuals. A pilot study in compensated cirrhotic patients showed a 65.4% increase in renal blood flow without systemic blood pressure effects[34]. Data on serelaxin in HRS is still limited.
HRS PREVENTION STRATEGIES
HRS prevention is achievable in several clinical contexts. In SBP, albumin volume expansion effectively mitigates circulatory dysfunction. A landmark study demonstrated that albumin administration in SBP significantly reduced renal failure development (10% vs 33%, P = 0.002) and 3-month mortality (22% vs 41%, P = 0.03)[9]. Evidence for albumin use in other infections beyond SBP is less robust, although one trial suggested a trend toward reduced renal failure in non-renal failure patients receiving albumin for infections other than SBP (3% vs 10%, P = NS)[35].
Albumin administration post-LVP (6-8 g albumin per liter of ascites removed) effectively prevents circulatory dysfunction worsening, minimizing impacts on electrolytes, creatinine, and renin levels. Albumin volume expansion also improves survival post-LVP and is recommended by international guidelines[36,37].
Primary antibiotic prophylaxis of SBP also prevents HRS. Fernández et al.[38] showed that SBP primary prophylaxis in advanced cirrhosis reduced HRS development (28% vs 41%, P = 0.02) and 3-month mortality (94% vs 62%, P = 0.003), likely due to norfloxacin’s effect in reducing gut bacterial product levels and bacterial translocation.
Alt text: Summary of key prevention strategies for hepatorenal syndrome in patients with advanced liver cirrhosis, including albumin administration during SBP and post-LVP, and antibiotic prophylaxis for SBP.
FUTURE RESEARCH DIRECTIONS IN HRS
HRS diagnosis is continuously evolving, currently relying on clinical criteria and serum creatinine, a suboptimal renal function marker. Future research must prioritize novel biomarkers, such as urinary NGAL, to improve HRS diagnostic accuracy and refine clinical algorithms. Increased research interest in this area is promising.
Identifying patients with low likelihood of response to current treatments is crucial for early initiation of alternative therapies and potential LT prioritization. Further research is also essential to explore novel treatments beyond terlipressin and albumin for this life-threatening condition.
CONCLUSION
HRS remains a critical decompensation in advanced liver cirrhosis with high short-term mortality. The HRS diagnosis criteria have been updated to incorporate AKI definitions, enabling earlier HRS diagnosis. Urinary NGAL shows promise in differentiating ATN and should be integrated into HRS diagnosis algorithms. Terlipressin and noradrenaline are currently the only effective medical treatments, with limited reversal rates (40%-50%). Early treatment initiation, facilitated by the new ICA HRS diagnosis criteria, is crucial. Novel therapies are urgently needed. LT remains the only curative option and should be considered for all eligible patients.
Footnotes
Manuscript source: Invited manuscript
Specialty type: Gastroenterology and hepatology
Country of origin: United Kingdom
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Conflict-of-interest statement: Acevedo JG and Cramp ME declare no conflict of interest related to this publication.
Peer-review started: October 2, 2016
First decision: October 20, 2016
Article in press: February 13, 2017
P- Reviewer: Ding MX, Fargion S, Sato T, Thomopoulos KC S- Editor: Song XX L- Editor: A E- Editor: Li D
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