INTRODUCTION Hepatorenal syndrome (HRS) is a subtype of functional acute kidney injury (AKI), recently renamed as HRS-AKI, that occurs in patients with cirrhosis and ascites. It is also a form of organ failure that contributes to the syndrome of acute-on-chronic liver failure (ACLF). Without timely treatment, the condition is fatal. In this review, we focus on recent updates on the definition, diagnosis, and management of HRS-AKI. Definition The recent recognition that a serum creatinine (sCr) level of ≥2.5 mg/dL (233µmol/L) could underestimate serious renal disease in patients with cirrhosis with sarcopenia has led to changes in the definition of renal dysfunction in cirrhosis. AKI uses a dynamic change in sCr to describe renal dysfunction in many stages depending on severity (Table 1).1 Its phenotypes can be categorized into either functional or structural etiologies (Figure 1). HRS-AKI is defined as AKI that fulfills all the other diagnostic criteria of HRS (Table 2).1 The measurement of urine output (UO) is not currently a part of the diagnostic criteria of HRS-AKI because patients with cirrhosis and ascites have low UO at baseline due to avid sodium and water retention. However, a recent study showed that reduced UO without sCr elevation results in a higher mortality in cirrhotic patients who were admitted into the intensive care unit when compared with using sCr measurements alone.2 TABLE 1 - Diagnostic criteria for acute kidney injury Parameter Definition Baseline sCr Stable sCr ≤3 mo If not available, a stable sCr closest to the current one If no previous sCr at all, use admission sCr Definition of AKI ↑ in sCr by ≥0.3 mg/dL (26.4 µmol/L) in <48 h; or ↑ 50% from baseline Staging Stage 1: ↑ in sCr by ≥0.3 mg/dL (26.4 μmol/L) in <48 h, or increase in sCr ≥1.5–2.0 times from baseline Stage 2: ↑ in sCr >2.0–3.0 times from baseline Stage 3: ↑ in sCr >3.0 times from baseline, or sCr >4 mg/dL (352 µmol/L) with an acute increase of ≥0.3 mg/dL (26.4 µmol/L), or the initiation of renal replacement therapy Abbreviations: AKI, acute kidney injury; sCr, serum creatinine. Adapted from Angeli et al1 with permission. FIGURE 1: Different phenotypes of renal dysfunction in patients with cirrhosis. Abbreviations: AKI, acute kidney injury, ATN, acute tubular necrosis, CKD, chronic kidney disease, HRS, hepatorenal syndrome, GN, glomerulonephritis. TABLE 2 - Previous and current definitions of hepatorenal syndrome Old Name New Name Definition HRS-1 HRS-AKI AKI diagnosis according to ICA-AKI criteria* Cirrhosis and ascites Absence of shock No current or recent use of nephrotoxic drugs (diuretics, NSAIDS) Absence of parenchymal kidney disease No proteinuria No hematuria No urinary cast Normal kidney ultrasonography HRS-AKD GFR<60 mL/min for<3 mo; or ↑ in sCr<50% within 3 mo HRS-2 HRS-CKD eGFR<60 mL/min for ≥3 mo *Refer to Angeli et al.1Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury, CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRS, hepatorenal syndrome, sCr, serum creatine. Adapted from Angeli et al1,3 with permission. Patients with cirrhosis, ascites and functional kidney injury, who do not meet the criteria for HRS-AKI, should be referred to as HRS-non-AKI.3 HRS-non-AKI is defined by estimated glomerular filtration rate rather than by sCr and is divided into HRS-acute kidney disease and HRS-chronic kidney disease (Table 2). With an increased prevalence of NASH with its associated conditions, such as diabetes and obesity, structural causes of renal disease are on the rise. Further acute renal functional changes may superimpose, causing acute-on-chronic renal failure. Diagnosis HRS-AKI is diagnosed using the International Club of Ascites consensus criteria after the exclusion of prerenal AKI (or prerenal azotemia) and structural kidney diseases (Figure 2A). Prerenal AKI can be diagnosed and treated by fluid challenge, but the ability to differentiate between HRS-AKI and structural causes of AKI, namely acute tubular necrosis, may be a clinical challenge. The development of biomarkers of renal injury may help.4 For example, a level of 220–244 µg of neutrophil gelatinase-associated lipocalin or NGAL per gram of creatinine is able to differentiate acute tubular necrosis from functional renal failure in 86% of cases.5FIGURE 2: (A) Diagnosis for patients presenting with acute kidney injury. *Precipitating factors: infections, large volume paracentesis without albumin administration, alcoholic hepatitis, nephrotoxic drugs, excess use of diuretics, gastrointestinal blood loss or other sources of fluid loss such as excessive diarrhea from over-zealous lactulose use. *HRS-AKI criteria according to ICA-AKI criteria (refer to Angeli et al1). (B) Suggested management algorithm for patients presenting with hepatorenal syndrome. Abbreviations: ACLF, acute chronic liver failure; AKI, acute kidney injury; HRS, hepatorenal syndrome; LT, liver transplantation; max, maximum; RRT, renal replacement therapy.Management The first step in the management of HRS-AKI is to remove and treat precipitant(s) to prevent further deterioration in renal function (Figure 2B). Common precipitants include infections, large volume paracentesis without albumin administration, alcoholic hepatitis, nephrotoxic drugs, excess use of diuretics, gastrointestinal blood loss, or other sources of fluid loss such as excessive diarrhea from over-zealous lactulose use. Albumin Albumin serves not only as a plasma volume expander but it also has positive cardiac inotropic effects through its anti-inflammatory and antioxidant properties. It is ineffective in reversing HRS on its own and is used in conjunction with vasoconstrictors in the management of HRS-AKI.6 A recent meta-analysis has found that a total of 600 g of albumin with vasoconstrictors given over the course of HRS treatment provided significant survival benefits compared with patients who received less.7 This may be explained by recent data that suggest that the inflammation suppressing the effect of albumin in advanced cirrhosis is more pronounced at higher doses.8 Patients should also be monitored for volume overload and pulmonary compromise.6 Vasoconstrictors Systemic vasoconstrictors include terlipressin, norepinephrine, a combination of midodrine and octreotide, and dopamine with furosemide. It has been estimated that the new definition of HRS-AKI will lead to the earlier initiation of treatment by 4 days, with possible improved outcomes.9 However, this is yet to be confirmed in future studies. Terlipressin Terlipressin is the most commonly used vasoconstrictor worldwide. It is a vasopressin analog that activates the V1a receptor on vascular smooth muscle cells resulting in splanchnic vasoconstriction. This decreases portal pressure through reduced portal inflow and intrahepatic resistance, thereby redistributing blood volume to the systemic circulation. This, together with an increase in systemic vascular resistance, can increase the mean arterial blood pressure and hence the renal perfusion pressure. Terlipressin may also ameliorate inflammation-induced vasodilation by reducing bacterial translocation.10 Terlipressin is administered at 0.5–1 mg every 4–6 hours as an intermittent bolus6 or 2 mg/d as a continuous infusion11 for up to 14 days. It can be stopped at day 4 if there is no response or if the sCr continues to rise despite the treatment. In patients who have <30% reduction in the sCr by day 4 of terlipressin, the dose is increased to maximum 12 mg/d in the absence of side effects. Patients who have a complete response by decreasing their sCr to <1.5 mg/dL (133 µmol/L) can have their terlipressin stopped before 14 days.6 Terlipressin has been evaluated in 4 randomized controlled trials (RCTs) in patients with cirrhosis, ascites, and HRS.12 The most recent CONFIRM study is the largest RCT, comparing terlipressin versus placebo, both with albumin.6 Verified HRS reversal, defined as a reduction of sCr to <1.5 mg/dL (133 µmol/L) with survival for at least 10 days without renal replacement therapy, was higher in the terlipressin group compared with placebo group (32% vs. 17% P=0.0006).6 Other published RCTs have demonstrated HRS reversal rate in 36%–44% of patients, with 2 of the other 3 studies showing a significant difference between the terlipressin and the placebo arms.12 None of the studies have shown a significant difference in survival, except for those who responded with a reversal of their HRS. Partial improvement of renal function with treatment, as indicated by a reduction in 1 stage of HRS-AKI was sufficient to provide a survival benefit.13 Positive predictors of response to terlipressin include pretreatment bilirubin of <10 mg/dL (170 μmol/L), baseline sCr of <5 mg/dL (440 μmol/L), lower stage of ACLF, and a sustained increase in the mean arterial pressure by 5–10 mm Hg with treatment.14–16 Patients with alcoholic hepatitis and sepsis responded better to terlipressin than placebo, as were those with systemic inflammatory response syndrome.6,10 Ischemic side effects are related to the vasoconstrictive effects of terlipressin. This can be reduced through continuous infusion administration as opposed to bolus dosing.11 The CONFIRM study demonstrated that fluid status should be monitored, as acute respiratory failure can occur in HRS patients treated with terlipressin and albumin, especially in those with grade 3 ACLF.17 To reduce the risk for respiratory failure with terlipressin use, it has been recommended that terlipressin should not be used in patients with grade 3 ACLF, as well as patients with pretreatment peripheral oxygen saturation of <90% on room air. Patients should be monitored with daily chest auscultation and at least every 4 hours for their oxygen saturation while receiving terlipressin, which should be stopped if the oxygen saturation falls below 90% on room air.17 Other vasoconstrictors Norepinephrine is an alpha-adrenergic receptor agonist and acts as a systemic vasoconstrictor. It has been shown to be equally effective as terlipressin in small RCTs, except in the setting of ACLF defined by the Asian Pacific region [international normalized ratio of >1.5, a serum bilirubin of >5 mg/dL (>85 µmol/L) together with the appearance of ascites and/or HE within 4 wk], where terlipressin yielded improved results.18 The combination of midodrine and octreotide has been shown to be ineffective as a treatment for HRS.19 Liver transplantation and simultaneous liver and kidney transplantation Liver transplantation (LT) is the definitive treatment of HRS-AKI, as it restores liver function and reverses the effects of portal hypertension. Simultaneous liver and kidney transplantation may be necessary for patients who are not expected to recover kidney function post-transplantation or in patients with underlying chronic kidney disease and hereditary renal conditions. The eligibility criteria for simultaneous liver and kidney transplantation in the US enable LT recipients a period of time after LT to allow for renal recovery and, at the same time, provide safety net prioritization of kidney transplantation in patients who have persistent or developed kidney dysfunction (Figure 3).20FIGURE 3: Organ procurement and transplantation network selection criteria for simultaneous liver kidney transplant for hepatorenal syndrome. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease, eGFR, estimated glomerular filtration rate, ESRD, end stage renal disease; HUS, hemolytic uremic syndrome; LT, liver transplantation, min, minute; sCr, serum creatine; SLKT, simultaneous kidney liver transplantation. Adapted from Formica et al.20CONCLUSIONS HRS-AKI is a life-threatening complication that requires early diagnosis and prompt initiation of treatment. Further studies are now refining the ideal population of patients to treat, the regimens to be used and newer vasoconstrictor molecules. Treatment response with terlipressin, even with a small reduction in sCr, had led to improved survival. Timely LT remains the definitive treatment, and the guidelines for SKLT are evolving.