Understanding acute kidney injury in cirrhosis: Current perspective

Abstract

Acute kidney injury (AKI) is present in 30%-40% of hospitalized patients with cirrhosis. Its incidence is higher in patients with severe alcoholic hepatitis, spontaneous bacterial peritonitis, and acute-on-chronic-liver failure (ACLF). Kidney injury is an important landmark event in the natural history of cirrhosis as it is associated with higher mortality. Overwhelming systemic vasodilation, cardiac dysfunction, hypoperfusion, endotoxemia, and direct nephrotoxicity predispose patients with cirrhosis to kidney injury. Infection is present in 25% of patients with decompensated cirrhosis and 35%-40% of patients with ACLF. Advanced cirrhosis with portal hypertension leads to a sluggish portal flow, leading to increased gut congestion, altered gut permeability and bacterial translocations. They drive infection and endotoxemia in such patients. Pathogen-associated molecular patterns activate inflammatory cascades, which leads to further deterioration in hemodynamics and reduced glomerular filtration rate. Infections and pro-inflammatory cytokines like interleukin 6 (IL-6), IL-1, and tumor necrosis factor alpha may directly cause kidney parenchymal injury. The combined effect of dysfunctional albumin and systemic and splanchnic vasodilatation leads to low effective blood volume, activating the renin-angiotensin-aldosterone system. This causes renal vasoconstriction, water retention, and ascites, which progresses to hepatorenal physiology and AKI development. Vasoconstriction and volume expansion effectively improve arterial blood volume and systemic hemodynamics, thereby improving renal blood flow. It is of paramount importance to predict, detect, and treat AKI in its early state, as progressive renal dysfunction is invariably associated with higher mortality in patients with decompensated cirrhosis and ACLF. This comprehensive review will focus on the recent evolving concepts of the pathophysiology, diagnosis, and management of AKI in patients with cirrhosis.

Key Words: Acute kidney injury; Acute-on-chronic liver failure; Ascites; Cirrhosis; Hepatorenal syndrome

Core Tip: The development of acute kidney injury (AKI) changes the trajectory of the natural history of patients with decompensated cirrhosis or acute-on-chronic-liver failure. With the discovery of newer biomarkers and a better understanding of hemodynamics in patients with AKI and cirrhosis, there is a paradigm shift in the management of such patients. This comprehensive review focuses on the current perspective of the pathophysiology, diagnosis, and management of patients with AKI in cirrhosis.

INTRODUCTION

Acute kidney injury (AKI) is associated with higher morbidity and mortality in patients with cirrhosis and imparts a significant healthcare burden[1-3]. The mechanism of AKI in cirrhosis is multifactorial[4,5]. Portal hypertension is associated with cirrhosis-associated immune dysfunction and increased intestinal translocation of bacteria, leading to overwhelming systemic vasodilation[5,6]. The inflammatory cycle perpetuates and enters a vicious cycle, which further deteriorates the hemodynamics, leading to hepatorenal syndrome (HRS)[7-10]. Vasoconstriction and volume expansion are effective in improving arterial blood volume and systemic hemodynamics, thereby improving renal blood flow (Figure 1). By contrast, pre-renal AKI responds only to volume expansion with albumin[11-13]. Hence, the cornerstone of treatment is combining volume expanders, splanchnic and systemic vasoconstrictors[13-15]. Terlipressin also helps to overcome the hemodynamic deficit, improve AKI, and mobilize ascites in patients with cirrhosis[16,17]. Differentiating prerenal or HRS-AKI from acute tubular necrosis (ATN) is important as ATN carries a poor prognosis, and vasoconstrictors can be detrimental in patients with ATN and cirrhosis[13]. Thus, it is important to predict, detect, classify, and treat AKI in its early state, as progressive renal dysfunction is invariably associated with higher mortality in patients with decompensated cirrhosis and acute-on-chronic liver failure (ACLF)[3].

Figure 1 Altered hemodynamic and targets of therapy in patients with acute kidney injury in cirrhosis. Increased intestinal permeability allows gut-derived lipopolysaccharides to enter the systemic circulation. Overwhelming systemic vasodilatation leads to a decrease in systemic vascular resistance and effective blood volume. Underfilling of the renal vasculature activates the renin-angiotensin-aldosterone system (RAAS) axis. RAAS activation leads to sodium retention, reduced glomerular filtration rate, and ascites. The quantitative defects in albumin contribute to decreased oncotic pressure and further worsen hemodynamics. Hence, albumin, along with splanchnic vasoconstrictors, is the mainstay of treatment in patients with hepatorenal syndrome. AKI: Acute kidney injury; EABV: Effective arterial blood volume; GFR: Glomerular filtration rate; PAMPs: Pathogen-associated molecular patterns; RARI: Renal artery resistive index; SVR: Systemic vascular resistance.

DIAGNOSIS OF AKI AND ITS PHENOTYPE

AKI in cirrhosis is diagnosed when there is an absolute increase of serum creatinine by 0.3 mg/dL or an increase of baseline serum creatinine by 50% (Table 1)[14,18]. Whereas Kidney Disease: Improving Global Outcome group defines AKI if any one of these is present in a patient: (1) An increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours; (2) An increase in serum creatinine to > 50%, which is known or presumed to have occurred within the prior 7 days; or (3) Urine output < 0.5 mL/kg/hour which is there for last 6 hours[19]. Lately, the International Club of Ascites (ICA) and Acute Disease Quality Initiative (ADQI) proposed new diagnostic criteria for HRS-AKI (Table 1)[14]. The decline in urine output precedes changes in serum creatinine, and oliguria is considered an independent predictor of worse outcomes. However, creatinine is an unreliable marker to detect kidney dysfunction in patients with cirrhosis due to the higher prevalence of sarcopenia among these patients; thus, newer biomarkers (see new biomarkers section) like cystatin-C have been used in patients with cirrhosis to predict AKI[20,21].

Table 1 Diagnosis of hepatorenal syndrome.

Key points of diagnosis
Cirrhosis with ascites
Increase in serum creatinine ≥ 0.3 mg/dL (26.5 mol/L) within 48 hours or ≥ 50% from baseline value known or presumed to have occurred within the prior 7 days and/or urinary output ≤ 0.5 mL/kg for ≥ 6 hours
Absence of improvement in serum creatinine and/or urine output within 24 hours following adequate volume resuscitation (when clinically indicated)
Absence of strong evidence for alternative explanation as the primary cause of AKI

AKI: Acute kidney injury.

After defining AKI, it is important to classify the type of AKI phenotype (Figure 2). Among 30% of hospitalized patients with cirrhosis and AKI, pre-renal AKI is the most common variety[1,2]. A detailed history regarding the use of diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), and angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) should be documented and discontinued (Figure 2). Prerenal AKI can also be precipitated by overzealous use of diuretics, diarrhea, vomiting, or any other form of blood or fluid loss from the body[22]. Intrinsic kidney disease can be caused by ATN, acute interstitial nephritis, and the use of any contrast during radiological evaluation[23,24]. AKI can evolve into acute kidney disease (AKD) or chronic kidney disease (CKD) if renal injury persists for more than 7 or 90 days, respectively (Figure 2). Concomitant liver and kidney disease can be present in various conditions and can give us a clue about the diagnosis of underlying CKD[24]. Intrinsic kidney disease and hypovolemia should be ruled out before diagnosing HRS-AKI.

Figure 2 Stepwise diagnostic algorithm of acute kidney injury in patients with cirrhosis. Routine and microscopic examination of urine, 24-hour urinary protein, and fraction urinary sodium excretion are the initial diagnostic modalities. Bedside point-of-care ultrasound, renal artery resistive index, and newer biomarkers can be used as additional supportive evidence to pinpoint a diagnosis of acute kidney injury (AKI) in cirrhosis and classify them. After acute interstitial nephritis and glomerulonephritis have been ruled out, volume expansion therapy with albumin is advocated. Patients who fail to respond to albumin after 48 hours of therapy should be classified as hepatorenal syndrome (HRS). Based on the last serum creatinine, they can be classified as HRS-AKI or HRS-non-AKI. AKD: Acute kidney disease; ATN: Acute tubular necrosis; CKD: Chronic kidney disease; e-GFR: Estimated glomerular filtration rate; HRS-NAKI: Hepatorenal syndrome-non-acute kidney injury.

Diagnosis of HRS is made when a patient with cirrhosis or acute liver failure meets the criteria of AKI (Table 1), and there is no improvement of renal function after withdrawal of nephrotoxic drugs and 48 hours of volume expansion with albumin[14,25]. However, this time duration is reduced to 24 hours as per the joint ICA and ADQI guidelines (Table 1) mentioned earlier[14]. The fractional excretion of sodium (FENa) is typically low in this group of patients (FENa < 0.2)[26,27]. Neutrophil gelatinase-associated lipocalin (NGAL) has been used to rule out ATN. Still, there is no standard marker to diagnose HRS; it is a diagnosis of exclusion[25]. HRS is a form of functional renal failure when there is kidney dysfunction without any structural damage. Recent data on patients with HRS have challenged the conventional functional nature of kidney injury. Some parenchymal and tubular changes may coexist in patients with HRS[28].

Older subtypes of HRS, HRS-1, and HRS-2, have been reclassified as HRS-AKI and HRS-non-AKI (HRS-NAKI), respectively (Table 1). Patients with cirrhosis and recent worsening of renal function, defined as an increase in creatinine by 0.3 mg/dL in 48 hours or by 50% within a week and/or decreased urine output (< 0.5 mL/kg for 6 hours or more), are classified as HRS-AKI. HRS-NAKI includes HRS-AKD and HRS-CKD based on the previous creatinine and estimated glomerular filtration rate (GFR) (Figure 2). HRS-CKD can be diagnosed if the patient’s baseline creatinine or GFR is available, which was done at least 3 months prior. Persistent GFR < 60 mL/minute/1.73 m² for more than 3 months should be defined as HRS-CKD if there is no evidence of structural kidney disease (Figure 2). The group of patients who fall between HRS-AKI and HRS-CKD are reclassified as HRS-AKD[14,25] (Table 1).

ROUTINE BLOOD AND URINARY TESTS

Routine urine examinations include urine for casts, dysmorphic red blood cells (RBCs), urinary sodium (U_Na) and urea (U_urea), and 24-hour urinary protein quantification[26] (Table 2). The FENa is low in patients with cirrhosis without AKI[26]. Very low FENa (< 0.1-0.2) is highly suggestive of HRS[25,26]. FENa is also important to differentiate between HRS-AKI and ATN[26]. The absence of significant proteinuria (24-hour urinary protein < 500 mg/day) and microhematuria (< 50 RBCs/high-power field [HPF]) can indicate that the patient does not have significant structural kidney disease (Table 2). However, recent data suggest that these parameters are not always useful to rule out structural kidney disease[28]. FEUrea is another useful marker to diagnose HRS and to classify the subtypes of AKI in cirrhosis ACLF[29]. FEUrea is highest in ATN, whereas a lower level is seen in pre-renal AKI and HRS. However, FENa performs better than FEUrea in classifying patients with AKI in cirrhosis (Table 2)[27]. FEUrea > 33% suggests ATN, whereas FEUrea < 21% is seen in pre-renal AKI[29]. The use of vasoconstrictors in patients with ATN can be detrimental as it may worsen the glomerular filtration rate[25]. So, it is mandatory to rule out ATN before starting the treatment of HRS. Pre-transplant ATN is associated with higher post-transplant mortality and kidney dysfunction (Table 2)[30].

Table 2 Serum biomarkers, urinary biomarkers, and hemodynamic parameters to differentiate among pre-renal acute kidney injury, acute tubular necrosis, and hepatorenal syndrome.

Parameters	Pre-renal AKI	Hepatorenal syndrome	Acute tubular necrosis	Comments
Clue to diagnose	History of fluid loss or overzealous use of diuretics	Presence of refractory ascites, hyponatremia	Presence of sepsis and hypotension	History cannot be always reliable to diagnose the subtypes of kidney injury
Urine sediments[73,74]	The lack of any casts suggests functional renal failure mostly pre-renal AKI[56]	Usually absent	Muddy brown casts and renal tubular epithelial cell casts	Should be interpreted by expert renal pathologists
	Sensitivity: 73%		RETC and granular cast
	Specificity: 75%		PPV: 100%
	However, bland, hyaline cast may be present		NPV: 40%
FENa[27,75]	< 1	< 1 for diagnosing HRS-AKI	Usually > 1	FENa is unable to distinguish between Pre-renal AKI and HRS-AKI
	Sensitivity: 90%	Sensitivity: 100%	Sensitivity: 89%	Not validated in patients on diuretics
	Specificity: 82%	Specificity: 14%	Specificity: 71%	FENa can be < 1 in patients with cirrhosis without AKI
	To differentiate between intrinsic vs pre-renal kidney injury	AASLD	FENa < 0.56 excludes ATN
		< 0.1 suggests HRS[46]
FEUrea[29]	< 21	< 28.7	> 33	No standardized cut-off in patients with cirrhosis
	Sensitivity: 90%	Sensitivity: 75%	< 34 to rule out ATN
	Specificity: 61%	Specificity: 83%	Sensitivity: 70%
	For PRA vs HRS	For non-HRS vs HRS	Specificity: 58%
NGAL-1[35,36,38,39]	< 110	< 100	> 194 mcg/g Cr
	Sensitivity: 88%		Sensitivity: 91%
	Specificity: 85%		Specificity: 82%
Renal artery resistive index[76,77]	Cannot differentiate between prerenal AKI and AKI-HRS	> 0.7 predicts HRS[76]	> 0.8 is suggestive of ATN[77]	RARI is higher in patients with cirrhosis and ascites compared to healthy individuals
		> 0.77 predicts HRS in cirrhosis	RARI is higher in ATN than in HRS.
		Sensitivity: 100%
		Specificity: 77%

AKI: Acute kidney injury; ATN: Acute tubular necrosis; Cr: Creatinine; FENa: Fractional excretion of sodium; HRS: Hepatorenal syndrome; NGAL: Neutrophilc-gelatinase associated lipocalin; NPV: Negative predictive value; PPV: Positive predictive value; PRA: Plasma renin activity; RARI: Renal artery resistive index.

LIMITATIONS OF ROUTINE BIOMARKERS

The absence of renal parenchymal disease is mandatory to diagnose HRS-AKI[25]. Moreover, in patients with ACLF, sepsis, and acute variceal bleeding, other causes for renal dysfunction may coexist (Table 2). Routine urinary biomarkers (i.e. urinary protein < 500 mg/day and RBCs < 50/HPF) are not always helpful in diagnosing structural kidney disease[31,32]. An insightful study by Trawalé et al[28] showed that the absence of proteinuria and hematuria is not very useful in ruling out intrinsic kidney disease. In that study, 18 patients with suspected HRS-CKD underwent kidney biopsies. They all had urinary protein < 500 mg/day and urinary RBCs < 50/HPF. However, the histology of those patients suggested the presence of intrinsic kidney disease in most of them (glomerular disease in 13 patients, vascular injury in 12 patients, and ATN in 12 patients). So, recent evidence suggests that HRS is a form of functional renal disease with some degree of renal parenchymal injury[28].

NEWER URINARY AND SERUM BIOMARKERS

Routine baseline evaluations may not always detect the degree of parenchymal injury[28,30]. Hence, different serum and urinary biomarkers have been used to detect, classify, and prognosticate patients with AKI and cirrhosis[33]. Novel biomarkers can be classified in different ways. Some biomarkers are related to kidney injury (kidney injury molecule-1 [KIM-1]) or cell cycle arrest (tissue inhibitor of metalloproteinase), whereas some may be associated with decreased GFR (cystatin C). Alpha-1 microglobulin, beta-M, and retinol-binding protein (RBP) are increased in AKI because of diminished tubular reabsorption of plasma proteins (Table 3)[33,34]. The most used biomarkers in AKI are cystatin-C, NGAL, and KIM-1[35-37]. NGAL has been used to predict AKI in patients with cirrhosis (Table 3). It is increased after 1 hour of ischemic injury to the kidneys[38,39]. NGAL has also been found to help differentiate between ATN and HRS-AKI[33,39]. Higher NGAL is seen in ATN. NGAL > 110 ng/mL is associated with high in-patient mortality[40]. In a study of 162 patients with decompensated cirrhosis and AKI, urinary NGAL predicted ATN and non-response to terlipressin in HRS-AKI and was an independent predictor of in-hospital mortality[4]. However, it can be high in patients with glomerulonephritis[41]. Cystatin-C is another promising marker that has been widely used as one of the earliest markers of AKI in patients with or without cirrhosis. Cystatin-C is a low molecular weight protein produced by all nucleated cells, filtered at the glomerulus, and reabsorbed by proximal tubular cells of the kidney. However, it is not affected by age, muscle mass, malignancy, or inflammation. Its assay is also not affected by high serum bilirubin levels. It increases before the peak of creatinine and detects AKI in its earlier phase. Higher cystatin-C is associated with a higher need for renal replacement therapy (RRT) and higher mortality[42]. An Indian study has shown similar results in patients with ACLF[43]. In that study, serum cystatin-C > 1.47 mg/dL is a better predictor of AKI than creatinine in patients with ACLF (Table 3). However, cystatin-C is not a reliable marker for differentiating ATN and HRS-AKI[42]. Higher levels correlate with mortality in patients with cirrhosis[44,45]. KIM-1 is a transmembrane protein in the proximal tubule and a relatively stable marker. It performs better than creatinine to detect early AKI[33,46]. KIM-1 level > 3.1 pg/mL is suggestive of HRS-AKI[47]. However, there is insufficient data to establish it as the renal marker to predict mortality (Table 3).

Table 3 Commonly used kidney biomarkers in patients with cirrhosis.

Newer markers	Role in differentiating between ATN and HRS	As a predictor of mortality	Role in diagnosing HRS-AKI	Comments
NGAL[35,36,38,39]	417 mg/g Cr in ATN and 76 ug/g Cr in HRS	uNGAL 110 ng/mL is associated with inpatient mortality[53]	Increased in 1-2 hours after ischaemic renal injury	Can be high in other diseases. Higher synthesis in the presence of sepsis. High in lupus nephritis, IgA nephropathy[41]
KIM-1[47,53]	Differentiate HRS from ATN; Cut-off: 15.4 ng/mL (AUC: 0.63); HRS: 3.1 pg/mL	No data	Early rise predicts AKI; Better marker than creatinine[53]	Not widely available
Cystatin C[42-45,55]	No data	Serum cystatin-C level of > 1.45 mg/L had the highest 90-day mortality (sensitivity and specificity of 66.7% and 68.4%)[44]. Cystatin-MELD score predicts mortality[45]	Predicts development of AKI in one year[55]; Serum cystatin-C > 1.47 mg/dL is an early marker of AKI in cirrhosis[44,45]	Higher reliability than Cr in patients with sarcopenia

AUC: Area under the curve; AKI: Acute kidney injury; ATN: Acute tubular necrosis; HRS: Hepatorenal syndrome; KIM-1: Kidney injury molecule-1; MELD: Model for end stage liver disease; NGAL: Neutrophil-gelatinase-associated lipocalin; RARI: Renal artery resistive index; uNGAL: Urinary neutrophil gelatinase-associated lipocalin.

More than half of patients with ACLF may have underlying kidney injury[48]. Diagnosing and phenotyping AKI in ACLF is challenging as it can be multifactorial[48,49]. Serum cystatin-C and NGAL have been used to detect and prognosticate AKI in patients with ACLF[50]. In another study, soluble cluster of differentiation 163 (CD163) and NGAL were found to predict 28 days of mortality in patients with ACLF[51,52].

Other kidney biomarkers, including L-type fatty acid binding protein, interleukin-18 (IL-18), N-acetyl glycosaminidase, and RBP, are used in clinical trials for research purposes[53-55]. They are not widely available[33].

These newer biomarkers have limitations. Almost all of these biomarkers provide information regarding the damage that already occurred to the renal parenchyma, which might be useful to predict the development of CKD in ACLF patients. With the exception of cystatin-C, other biomarkers are mostly used in clinical trials. There is a great need for the development of cost-effective biomarkers that predict AKI in patients with cirrhosis. Recent developments should focus on discovering newer biomarkers that can monitor the metabolism of renal epithelial cells before their death.

ULTRASONOGRAPHY AND DOPPLER

Ultrasonography of kidneys

Routine ultrasonography of the kidney is useful for detecting CKD in patients with cirrhosis[56]. Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced fibrosis are at higher risk of CKD[57]. Bilateral shrunken or enlarged kidneys and loss of corticomedullary differentiation point toward the presence of structural kidney disease[56-58]. Based on ultrasonogram (USG) findings, a diagnosis of CKD can be made in patients with high creatinine who do not have baseline creatinine values.

Renal artery resistive index

Renal artery resistive index (RARI) is an important non-invasive parameter to predict pre-renal AKI in patients with cirrhosis. The renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system increase renal artery resistance in patients with cirrhosis and refractory ascites. RARI increases proportionately with Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), and MELD-sodium scores in patients with cirrhosis[59]. Lower RARI predicts better renal functions[60]. RARI is higher in patients with cirrhosis compared to healthy individuals. RARI > 0.7 is one of the predictors of AKI in cirrhosis. However, it may be fallacious in patients with systemic hypertension with underlying MASLD-related cirrhosis, intrinsic kidney disease, and generalized atherosclerotic disease[61,62].

RARI is a simple bedside tool to predict AKI in cirrhosis and it can also detect the phenotype of AKI in cirrhosis. A cut-off of > 0.7 can be taken as the predictor of pre-renal AKI in cirrhosis. Very high RARI (> 0.8) is often seen with ATN and may be helpful to differentiate between HRS-AKI and ATN[59,60].

Inferior vena cava diameter and collapsibility index

Bedside evaluation of inferior vena cava diameter (IVCD) and IVC collapsibility index (IVCCI) is used in diagnosing systemic hypovolemia in patients with cirrhosis[63]. IVCCI is calculated as (IVC_{maximum diameter} - IVC_{minimum diameter})/IVC_{maximum diameter} and varies between 12% and 42%. IVCCI > 50% and diameter < 0.7 cm suggest hypovolemia[64]. IVCD correlates with right atrial pressure. IVCD > 2 cm and IVCCI < 40% are suggestive of fluid overload status. Albumin infusion in this scenario can be detrimental[65].

In a study by Kaptein et al[64], of the 20 patients with a presumed diagnosis of HRS, 6 had hypovolemia as assessed by USG Doppler. This point-of-care test may help us avoid misclassifying hypovolemic patients as HRS[65]. However, there is no standardized cut-off of IVCD and IVCCI in patients with cirrhosis. Often, it can be fallacious in patients with grade 3 ascites[66].

Cardiac dysfunction and biomarkers in patients with AKI and cirrhosis

The presence of cardiac dysfunction and cirrhotic cardiomyopathy (CCM) influences the outcome in patients with ACLF[67]. Baseline cardiac dysfunction is associated with worsening HRS. Cirrhosis is often associated with diastolic failure, electromechanical dissociation, and impaired contractility. Ejection fraction alone is not sufficient to determine the spectrum of cardiac dysfunction[68,69]. Point of care two-dimensional (2D) echocardiography may be useful to estimate systemic vascular resistance index, cardiac index, e'velocity, and the presence of CCM. Very low systemic vascular resistance (SVR) predicts poor outcomes in patients with ACLF. In this group of patients, vasoconstrictors may help to counteract the overwhelming systemic vasodilation[70,71]. A previous study from our group showed that adding a second vasoconstrictor (noradrenaline after terlipressin if SVR < 700 dynes - second/cm⁵) was beneficial in improving renal function, ascites mobilization, gut permeability, and hemodynamics[7]. Point of care 2D echo may also detect reduced ejection fraction, where we should use albumin more judiciously to avoid volume overload[72].

MANAGEMENT OF AKI IN DECOMPENSATED CIRRHOSIS AND ACLF

General measures

After proper work-up, the management of renal dysfunction depends on the phenotype of AKI in patients with cirrhosis[73-77]. All offending drugs should be stopped to avoid ongoing nephrotoxicity. It includes beta-blockers, diuretics, ACEIs/ARBs, and NSAIDs[22,23,25,78]. Any potential source of extravascular fluid loss should be identified and corrected (Figure 2). Overzealous use of diuretics precipitates prerenal AKI[22,25]. Any clinical signs of dehydration, such as mean arterial pressure (MAP), pulse, orthostatic changes in blood pressure, capillary refill, skin turgor, decline in urine output, or mentation, should be carefully assessed. Volume replacement usually corrects kidney dysfunction in this scenario. Patients should be thoroughly screened for any infection, especially spontaneous bacterial peritonitis (SBP), pneumonia, and urinary tract infection. Empirical broad-spectrum antibiotics should be started when infection is suspected[78,79]. It has been shown to reduce the incidence of worsening AKI[6,79]. Patients with cirrhosis and septic shock should receive broad-spectrum antibiotics and volume resuscitation. Albumin can be preferred over 0.9% normal saline in patients with cirrhosis and sepsis[80]. A higher MAP goal is desirable in patients with renal dysfunction. Intradialytic hypotension is less in patients with higher MAP compared to patients with lower MAP. However, there is no survival benefit with higher MAP[81].

Pre-renal AKI responds to fluid therapy (Figure 2). After stopping all the nephrotoxic drugs and volume expansion, treatment of HRS can be initiated. Structural kidney disease should be ruled out in such patients.

Vasoconstrictors in HRS

Terlipressin: Terlipressin administered as a continuous infusion is the drug of choice for patients with HRS[25,82]. It is a pro-drug and is cleaved by endothelial peptidase to its active form. Its active form, lysyl-vasopressin, counteracts overwhelming splanchnic vasodilation (Figure 1) and increases renal blood flow[83]. Up to 20% of patients may have side effects, including diarrhea and abdominal cramps[82,83]. Adverse events are more common in patients with relatively preserved liver function[82]. A recent randomized controlled trial (RCT) (2 mg/24 hours infusion vs 0.5 mg every 4 hours initially then to a maximum dose of 12 mg/day plus albumin 20-40 g/day) has shown that infusion is equally effective in reversing HRS compared to intravenous (IV) bolus injections (76% vs 65%; P non-significant)[84]. However, terlipressin infusion is associated with a lesser rate of adverse events (35% vs 62%; P < 0.025)[84].

In a recently published randomized trial, the e-Terli study by Jindal et al[85] showed that the initiation of terlipressin as early as 12 hours has better outcomes in reversing HRS in ACLF patients. AKI response on day 7 was observed in 68.6% of patients compared to 31.4% of patients in the standard treatment arm.

Noradrenaline: Noradrenaline is an attractive alternative to terlipressin for patients with HRS-AKI. Noradrenaline is given at a dose of 0.5-3 mg/hour in infusion[86]. An RCT has demonstrated that noradrenaline is equally effective in reversing HRS compared to terlipressin. It is also associated with fewer side effects[86]. Patients with HRS-AKI who were managed with noradrenaline had a reversal rate of 43% (39% in the terlipressin group; P = 0.76). In multivariate analysis, a higher CTP score was associated with a lower response to vasopressor. Patients who responded to the treatment had a higher mean arterial pressure, urine volume and urinary sodium and low plasma renin activity. Noradrenaline, with a median dose of 13.1 mg/day, was cheaper than terlipressin (275 vs 975 euros) with similar efficacy. The terlipressin group also reported adverse events such as abdominal pain, peripheral cyanosis, and arrhythmia. However, there was no difference in short-term survival between the two groups. Data comparing noradrenaline and terlipressin for HRS is based on this RCT alone. Further studies and meta-analyses are required to validate its routine use.

In another RCT by Singh et al[87], patients who did not respond to terlipressin after 48 hours were randomized to receive either terlipressin alone or terlipressin combined with noradrenaline. There were no significant differences in the response rate (50% vs 76.7%; P = 0.06) and mortality (36.7% vs 53.3%; P = 0.13) between the two groups. Adverse events were more frequent in the terlipressin group (36.7% vs 13.3%; P < 0.05). SVR-guided titration or adding a second vasoconstrictor can be more useful in this scenario; however, more data are warranted on this issue[7].

Octreotide and midodrine: The combination of octreotide, albumin, and midodrine has been used in patients with HRS-AKI and HRS-NAKI. Previously, it was shown to improve short-term survival and renal function[88]. However, recent data suggest that this combination is not better than terlipressin and albumin regimens in reversing HRS. In an RCT by Cavallin et al[89], 70.4% of patients who received terlipressin (3 mg/day to a maximum of 12 mg/day) and albumin recovered from AKI, compared to 28.6% of patients who received octreotide (100 mcg three times daily to a maximum dose of 200 mcg three times daily and midodrine 7.5 mg three times daily to 12.5 mg three times daily). The results of this RCT suggest that patients with HRS should receive terlipressin if there are no contraindications. Octreotide and midodrine can be used where terlipressin is not available or contraindicated.

The effective blood volume is low in patients with cirrhosis in the background of systemic vasodilation (Figure 1)[90-92]. Reduced albumin and its transcriptionally modified forms bind less to the drugs and cytokines[93,94]. In addition to its role in maintaining oncotic pressure, albumin has many pleiotropic effects in cirrhosis[95]. A large RCT showed the superiority of 5% human albumin over normal saline for initial resuscitation in critically ill patients with cirrhosis and septic shock[6]. In patients with AKI and cirrhosis without any features of shock, volume expansion is done with 1 g/kg/day albumin for 48 hours. A dose of 20-40 g/day is recommended for use with vasoconstrictors in HRS-AKI[25,96]. Patients with CKD and heart failure are at a higher risk of developing volume overload after albumin infusion. Bedside lung ultrasonography, 2D echo, pro-N-terminal-brain natriuretic peptide, and point-of-care ultrasonography (POCUS) of IVCD and IVCCI are useful methods to detect volume overload states in such patients[63,97].

Transjugular intrahepatic portosystemic shunts

Transjugular intrahepatic portosystemic shunts (TIPS) have been used in refractory ascites and AKI in patients with cirrhosis[25,98]. This group mainly comprises patients with HRS-NAKI (previously called HRS-2). Patients with advanced liver dysfunction managed with TIPS have a higher incidence of hepatic encephalopathy (HE) and mortality[99]. Data on the feasibility and efficacy of TIPS in HRS is limited[99,100], so TIPS is currently not recommended for this indication.

Molecular adsorbent recirculating system and PROMETHEUS

Molecular adsorbent recirculating system and PROMETHEUS are extracorporeal artificial liver support systems[101]. They have been used in patients with liver failure[102]. However, none of these systems demonstrated any mortality benefits[103]. Currently, MARS and PROMETHEUS are not recommended for use in AKI with cirrhosis.

RRT

Patients with AKI and cirrhosis who fail to respond to vasoconstrictors and albumin have a very high mortality[82,83]. Liver transplantation or combined liver and kidney transplantation is their only option; however, a significant number of patients die while waiting for LT[104]. So, patients should undergo RRT while on a waiting list for LT because, without transplantation, mortality may reach up to 85% in these patients[104,105].

Liver and combined liver-kidney transplant

The presence of AKI, especially pre-transplant ATN, is associated with higher mortality following liver transplant[106]. One-fifth of such patients die within 6 months of transplant[107]. Combined transplants of the liver and kidney are recommended in patients with cirrhosis who are dialysis-dependent or have underlying significant proteinuria and CKD[108]. Current recommendations suggest a combined transplant if a patient with cirrhosis has evidence of CKD (calculated GFR < 60 mL/minute for > 90 days), or sustained AKI (on dialysis at least once a week, or calculated GFR < 25 mL/minute at least once every 7 days) or there are metabolic disorders like hyperoxaluria, atypical hemolytic uremic syndrome, and methylmalonic aciduria[108-110].

PREVENTION OF AKI IN CIRRHOSIS

Prevention of infection and appropriate antibiotic prophylaxis

Infection is the most common precipitant of ACLF[6,8,111]. Endotoxemia with superimposed bacterial infection worsens hemodynamics, resulting in a reduced GFR[112]. Any decrease in urine output and U_Na during the therapy should prompt physicians to look for any bacterial infection[7,113]. A thorough screening for hospital-acquired infection should be done[6,7]. Along with procalcitonin, novel biomarkers like CD64 and presepsin can be used to detect early bacterial infection[114,115]. Low protein in ascites is associated with higher risks of developing SBP[116]. Antibiotic prophylaxis should be started in these patients. Patients with acute variceal bleeding should also receive antibiotic prophylaxis for 7 days[117]. A recent RCT from India showed that norfloxacin prophylaxis is associated with a reduced incidence of infection in patients with ACLF[118]. However, it is currently not recommended for patients with ACLF. IV n-acetyl cysteine (NAC) and granulocyte-colony stimulating factor (G-CSF) have been shown to prevent AKI in cirrhosis[119,120]. They are not currently recommended for this purpose.

Specific indications of antibiotic prophylaxis in patients with cirrhosis are ascites with very low ascitic fluid protein, secondary prophylaxis in SBP, and following acute variceal bleeding in patients with CTP-B and CTP-C cirrhosis.

Role of antioxidants and NAC

NAC has been shown to reduce contrast-induced AKI in patients with sepsis and cirrhosis[120]. In an RCT comparing the combination of glucocorticoids and NAC vs glucocorticoids, a significant reduction in the incidence of HRS (25% vs 12%, 0.41, 95% confidence interval [CI]: 0.17-0.98; P = 0.02) and mortality due to HRS (22% vs 9%, 2.79, 95%CI: 1.08-7.42,;P = 0.02) was observed with NAC[121]. However, currently, there are no sufficient data to recommend the use of antioxidants or NAC for the prevention of AKI in patients with ACLF or decompensated cirrhosis.

Role of albumin

Albumin has a role in the prevention of AKI in patients undergoing therapeutic paracentesis, especially large volume paracentesis and those having SBP. In an RCT of 80 patients with ACLF, who underwent therapeutic paracentesis of < 5 L, paracentesis-induced circulatory dysfunction was more common in the non-albumin group as compared to the albumin group (70% vs 30%; P = 0.001), including a higher rate of AKI as well (62.5% vs 27.5%; P = 0.003)[9].

Sort et al[122] randomized 126 patients with SBP into two groups: the first group received 20% albumin at a dose of 1.5 g/kg at diagnosis and 1 g/kg on day 3 in infusion + cefotaxime, and the second received cefotaxime alone. The incidence of AKI was higher in the group without albumin (33% vs 10%; P = 0.002), and so were the in-hospital and 90-day mortalities (41% vs 22%; P = 0.03).

Avoidance of nephrotoxic drugs and contrast-induced nephrotoxicity

Patients with cirrhosis should be counseled about the potential harm of taking NSAIDs, ACEIs/ARBs, other over-the-counter medications, and complementary alternative medicines[123]. About 5% of patients with cirrhosis develop AKI after contrast injection. Lower bicarbonate levels and advanced cirrhosis are risk factors for developing AKI[124]. Albumin, NAC, and IV bicarbonate have been used to prevent AKI in cirrhosis; however, data are limited. Contrast-enhanced imaging should be done judiciously in patients with advanced liver disease.

Role of G-CSF

Currently, few RCTs have evaluated the effect of G-CSF on patients with ACLF, with heterogeneous data from Asian studies contradicting the data from European studies[125,126]. Currently, it is not recommended for the prevention of AKI in ACLF.

Maintaining effective arterial blood volume and addressing the underlying cardiac abnormality

Effective arterial blood volume is low in patients with cirrhosis[127]. Any intravascular fluid loss should be corrected promptly. It has been shown to prevent AKI and ATN. IV albumin can be useful in patients with septic shock. Concomitant hepatopulmonary syndrome, portopulmonary hypertension (PPH), and cardiomyopathy reduce cardiac output and activate RAAS. Beta-blockers should be discontinued in patients with PPH[128,129]. Cardiorespiratory comorbidities are often difficult to treat in patients with cirrhosis and may require LT[129].

MANAGEMENT OF CONCOMITANT AETIOLOGY

Concomitant liver and kidney disease can be found in patients with MASLD (diabetic kidney disease), viral hepatitis (glomerulonephritis), primary biliary cholangitis (interstitial nephritis), and alcoholic hepatitis (immunoglobulin A nephropathy)[57,130]. Treating the underlying etiology can reverse the outcome in these patients. Persistent kidney dysfunction and the need for RRT are indications of combined liver and kidney transplantation.

CONCLUSION

The management of AKI in cirrhosis often requires a multidisciplinary approach. Early detection of AKI may reverse the outcome in patients with cirrhosis. Proper clinical inquiry about nephrotoxic drugs, and proper use of appropriate biomarkers may identify the progression of kidney injury in such patients. POCUS is an evolving diagnostic modality to assess the volume status of patients with cirrhosis and AKI. RARI index can be used in selective groups of patients, however, more data is warranted on POCUS and RARI. Concomitant structural kidney disease may coexist in patients with cirrhosis. Ruling out other etiologies like ATN, structural kidney disease and pre-renal volume responsive AKI is the most important step in diagnosing HRS. The concept that HRS is a functional renal injury has been challenged as some degree of parenchymal injury may coexist with HRS. Routine biomarkers have limited value in diagnosing them. Cystatin-C and NGAL are the most used newer biomarkers to detect structural injury to the liver, however, they are not without limitations. Volume expansion with vasoconstrictors remains the cornerstone of the treatment in patients with HRS. Careful use of terlipressin in AKI is important as it may worsen renal function in patients with ATN. Preventing infection, judicious use of antibiotics and albumin may prevent AKI in patients with cirrhosis. TIPS can be used in a selective group of patients with HRS, however its indication is evolving. Concomitant liver-kidney transplantation can salvage a subset of patients who have persistently low GFR or structural kidney disease requiring hemodialysis. Current research should focus on hepato-renal hemodynamics and early serum or urinary markers to predict AKI in patients with cirrhosis.

ACKNOWLEDGEMENTS

The authors express their heartfelt gratitude to all the individuals who contributed their insightful intellectual assistance to this work.