AKI among individuals with cirrhosis is common, and it has been occurring more frequently over the last two decades. This has been observed among hospitalized patients with cirrhosis, where the burden of AKI has increased approximately 200% since 2004 and the burden of CKD has increased approximately 50% since 2004. Among liver transplant candidates, the burden of CKD has increased >200% since 2002, and the utilization of simultaneous liver-kidney transplantation has increased approximately 500% since 2000 (1,2). These trends are concerning because AKI and CKD are associated with poor clinical outcomes (1,3–5). For instance, patients with AKI or AKI superimposed on CKD have approximately three times greater mortality than those with either CKD alone or no kidney dysfunction (4,5). In addition, there is a growing recognition that episodes of AKI have a long-term effect on patients with cirrhosis. These episodes of AKI often lead to acute kidney disease, an indeterminate phase where it is not clear whether patients will achieve AKI reversal or acquire CKD (6). This interdependence between AKI and CKD has been established in cirrhosis. Patients with CKD are more likely to develop AKI (i.e., AKI on CKD) and less likely to have AKI reversal; similarly, those with AKI are more likely to develop CKD (7). It is hypothesized that the emergence of nonalcoholic fatty liver disease and its associated comorbidities (e.g., hypertension and diabetes mellitus) has led to a population with a greater susceptibility and decreased physiologic reserve to recover from AKI (2,7). These data highlight the importance of identifying the acuity, etiology, and severity of kidney dysfunction in patients with cirrhosis; the recognition of these independent syndromes has led to the proposal of a new nomenclature for the hepatorenal syndromes (Table 1).
Table 1. -
Definitions of AKI, hepatorenal syndrome type 1/hepatorenal syndrome-AKI, acute kidney disease, and CKD
||Hepatorenal Syndrome Prerequisites
||Stage 1: increase from baseline
sCr of either ≥0.3 mg/dl in 48 h or ≥1.5–1.9× baseline in the last 7 d or urinary output ≤0.5 mg/kg body weight in ≥6 h
Absence of shock
No treatment with nephrotoxic medications
No response to volume expansion
Absence of parenchymal disease (proteinuria: >500 mg/d; hematuria: <50 RBCs per HPF)
Suggestion of kidney vasoconstriction with FENa<0.2%
|Stage 2: ≥2–2.9× baseline sCr
|Stage 3: ≥3× baseline sCr or sCr≥4 mg/dl or KRT
||eGFR<60 ml/min per 1.73 m2 for <3 mo
||eGFR<60 ml/min per 1.73 m2 for ≥3 mo
HRS-1, hepatorenal syndrome type 1; sCR, serum creatinine; RBC, red blood cell; HPF, high-powered field; FENa, fractional excretion of sodium; AKD, acute kidney disease; HRS-2, hepatorenal syndrome type 2.
aBaseline sCr is defined as a stable sCr ≤3 months from the previous. If not available, a stable SCr closest to the current one. If no previous SCr at all, use the admission SCr.
bThere are limited data regarding albuminuria in patients with cirrhosis; however, it is presumed that patients with cirrhosis follow the general nephrology literature regarding mortality risk with proteinuria. It is not clear if patients with cirrhosis follow the same thresholds.
Assessment of Kidney Function in Cirrhosis
Estimating GFR utilizing serum creatinine–based formulas is inaccurate in patients with cirrhosis (8). Serum creatinine concentration in cirrhosis is affected by decreased hepatic synthesis of creatine and cirrhosis-related loss of skeletal muscle (8). As a result, serum creatinine is inherently lower, and consequently, the eGFR is often greater than measured GFR (9). These limitations of commonly used eGFR estimators have led to the development of two cirrhosis-specific estimators: the Royal Free Hospital and the GFR Assessment in Liver Disease estimators (10,11). They represent an improvement in GFR estimation; however, they do not account for some limitations of serum creatinine (12). To address these limitations, cystatin C has been studied, although without the creation of a cirrhosis-specific GFR estimator; instead, studies have focused on cystatin C as a predictor for AKI or mortality (13). In a recent meta-analysis, equations combining creatinine and cystatin C were the least biased (14).
Evaluation of AKI in Cirrhosis
Acute impairment in kidney function is clinically assessed by changes in serum creatinine and/or urine output (15). History and physical examination remain the cornerstones of the approach to diagnosis and dictate the pretest probability of a specific etiology of AKI. The clinical context (i.e., inpatient versus outpatient) often will inform the differential, including consideration for hepatorenal syndrome type 1 (HRS-1), a form of AKI unique to cirrhosis (Figure 1). Urine chemistries, complete urinalysis, and microscopic examination of the urinary sediment are essential elements of laboratory testing. Kidney ultrasonography is routinely used to rule out obstructive uropathy as a cause of AKI. Urine biomarkers have been tested to assess AKI in cirrhosis. These include neutrophil gelatinase–associated lipocalin, liver fatty acid–binding protein, kidney injury molecule-1, and tissue inhibitor of metalloproteinases-1, among others (Table 2) (16). These metrics capture either the degree of injury or the inflammatory response and have been linked with clinical outcomes. Prerenal azotemia and acute tubular injury combined account for the majority of the cases of AKI in cirrhosis. Although early reports linked HRS-1 to worse clinical outcomes than other AKI causes, a recent study reported similar 90-day mortality in HRS-1 compared with patients with acute tubular injury (17,18). Although clinical presentation and laboratory testing should point to specific etiologies, often clinically, these etiologies are challenging to distinguish, and they may overlap (19).
Table 2. -
Kidney biomarkers investigated as diagnostic tools for AKI in the setting of cirrhosis
||Nephron Damage Site
||Area Under Curve: Acute Tubular Ischemia versus Prerenal/Hepatorenal Syndrome
||Acute Tubular Ischemia
NGAL, neutrophil gelatinase–associated lipocalin; ↑, mild increase; ↑↑, moderate increase; ↑↑↑, marked increase; —, no data available; KIM-1, kidney injury molecule-1; L-FABP, liver-type fatty acid–binding protein; TIMP-2, TIMP metallopeptidase inhibitor 2; IGFBP7, insulin-like growth factor binding protein 7; NS, nonsignificant; NR, none reported; miR-21, microRNA-21; miR-210, microRNA-210; ↓, mild decrease; ↓↓, moderate decrease; ↓↓↓, marked decrease; miR-146a, microRNA-146a.
These data are extrapolated from studies that compared biomarker levels between different etiologies of AKI. Only NGAL, miR-21, mir-210, miR-146a, adrenomodulin, and thromboxane A2 were compared between prerenal, hepatorenal syndrome-AKI, and acute tubular ischemia (ATI). All others were compared between ATI and non-ATI (64–69
). TIMP-2/IGFBP7 was compared between hepatorenal syndrome type 1 and no AKI (70
Etiology-Driven Management of AKI in Cirrhosis
Prerenal Azotemia and Ischemic Acute Tubular Injury
Individuals with decompensated cirrhosis are susceptible to prerenal azotemia resulting from gastrointestinal fluid losses induced by laxatives prescribed for prophylaxis for hepatic encephalopathy. In addition, urinary losses caused by diuretics prescribed for refractory ascites or secondary to poor cardiac output due to superimposed cardiorenal syndrome can lead to prerenal AKI (20). Ischemic acute tubular injury can result from prolonged prerenal azotemia or hemorrhagic shock due to variceal bleeding or be secondary to infections, like spontaneous bacterial peritonitis or septic shock (21). Urine sediment microscopy in cases of acute tubular injury often reveals the presence of characteristic muddy brown granular casts (22).
Regardless of the etiology or severity of prerenal azotemia, the treatment is centered on volume resuscitation. Intravascular assessment of volume status is often complex in patients with cirrhosis. A trial period of 24–48 hours of targeted volume resuscitation with albumin has been traditionally recommended. However, routine administration of volume expanders without a reasonable grasp on volume status might pose a risk of pulmonary edema (23,24). A combination of history, physical examination, laboratory data, and point-of-care ultrasound (POCUS) optimizes volume status assessment. In a single-center retrospective study with patients diagnosed with HRS-1, POCUS-based assessment led to the reclassification of the AKI etiology according to inferior vena cava diameter and collapsibility. Specifically, 21% of patients who were previously deemed clinically euvolemic had findings consistent with hypervolemia, and 23% exhibited hypovolemia despite presumed adequate volume resuscitation, suggesting the diagnostic utility of POCUS in this setting (25).
Hepatorenal Syndrome Type 1
HRS-1 is a unique form of AKI in patients with cirrhosis, portal hypertension, and ascites. The state of portal hypertension, peripheral arterial vasodilation, and decreased effective circulatory volume is associated with overactivation of the sympathetic nervous system and the renin-angiotensin system as well as marked renal vasoconstriction. The degree of kidney dysfunction required by the International Club of Ascites for the diagnosis has evolved over time. Currently, the definition adheres to the existing Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI (i.e., it is currently defined as greater than or equal to stage 1 AKI and/or a decrease in urine output to ≤0.5 ml/kg body weight in ≥6 hours) (Table 1) (15). A diagnosis of HRS-1 is often difficult to make. Unclear baseline serum creatinine values or clinical presentations not fitting the classic phenotype of hypotension, ascites, oliguria, and bland urinary sediment often make the diagnostic approach a challenging task. Moreover, often these patients have several competing risk factors for AKI that confound the clinical picture. These include infectious complications, nephrotoxic medications, acute tubular injury, etc. Nevertheless, in the correct clinical context, the diagnosis of HRS-1 can be made with some certainty.
Several risk factors have been identified as predictors of HRS-1. (1) Baseline serum creatinine. Patients with higher serum creatinine are more likely to develop HRS-1 and less likely to have AKI reversal (2,26). (2) Systolic BP. Patients with lower mean arterial pressure (MAP) at baseline are more likely to develop HRS-1 and less likely to achieve AKI reversal (27). (3) Other hemodynamic parameters, such as the evolution of hepatocardiorenal derangements. Prolonged maintenance of a hyperdynamic state leads to decreased cardiac responsiveness and diastolic dysfunction and ultimately predisposes patients to circulatory dysfunction and the development of HRS-1 (20). (4) Acute-on-chronic liver failure, a syndrome of acute and severe hepatic decompensation with associated multiorgan failure that occurs after several types of triggers (e.g., bleeding and infection) in patients with decompensated cirrhosis (28). Kidney dysfunction occurs in >50% of those patients hospitalized with acute-on-chronic liver failure—often a consequence of a precipitating event (e.g., infection and hemorrhage). Specifically, spontaneous bacterial peritonitis is a frequent cause of AKI and acute-on-chronic liver failure, and as such, the empirical use of albumin has been shown to prevent AKI and HRS-1 among patients with spontaneous bacterial peritonitis (29).
The treatment of HRS-1 centered on reversing hemodynamics. This has focused mainly on vasoconstriction, and tested agents include ornipressin, vasopressin, midodrine/octreotide combination, terlipressin, and norepinephrine (20). Regardless of the vasoconstrictor of choice, several key factors have emerged, which appear to dictate outcomes (Figure 2): (1) timing of initiation (the earlier in the disease evolution [i.e., at lower stages of AKI], the greater the likelihood of response to therapy) (26); (2) the effect on MAP (there is a nearly linear correlation between the increase in MAP and the likelihood of HRS-1 reversal; although the ideal MAP target is not clear, an increase of ≥15 mm Hg has been associated with improved outcomes) (30,31); (3) the degree of underlying liver disease (patients with an elevated total bilirubin level are less likely to respond to therapy; whether this is a direct effect of bile acid nephrotoxicity or a reflection of the underlying severity of illness is not known) (20); (4) reversal of the trigger (whether infection, hemorrhage, or another trigger, removal and treatment of the trigger dictate clinical outcomes); and (5) underlying cirrhotic cardiomyopathy or portopulmonary hypertension (underlying cirrhotic cardiomyopathy or portopulmonary hypertension plays an important role in determining if a patient will respond to vasoconstrictor therapy and have HRS-1 reversal).
On the basis of clinical trial evidence, norepinephrine and terlipressin are the most effective agents to treat HRS-1. Studies to date have varied in sample size, the severity of AKI at initiation, the degree of hepatic decompensation, interventions selected, and primary outcomes chosen. This variation has made it difficult to directly compare between vasoconstrictors, except for the more potent vasoconstrictors (i.e., norepinephrine and terlipressin) showing a greater likelihood of reversal. Most recently, the CONFIRM trial randomized 300 patients to either terlipressin or placebo (23). Results demonstrated a higher rate of hepatorenal syndrome reversal with terlipressin as compared with the placebo group (32% versus 17%; P=0.006); however, the treatment group had higher rates of respiratory failure (10% versus 3%). It is not clear if this was a direct effect of terlipressin or related to increased albumin-based resuscitation in the treatment group (32). In addition to terlipressin, ornipressin and vasopressin have been examined in HRS-1 in small and uncontrolled studies (33,34). However, lack of strong evidence, V1 receptor selective (of vasopressin), and concerns for adverse effects may have mitigated the enthusiasm for those alternative vasopressin analogs.
Currently, terlipressin is not approved by the Food and Drug Administration in the United States. As a result, norepinephrine is the preferred agent for HRS-1 in patients in an intensive care unit. However, norepinephrine cannot be administered on the general wards. Thus, the combination of midodrine and octreotide is routinely used to treat HRS-1 outside of the intensive care unit. Interestingly, the use of midodrine and octreotide use originated from a nonparallel controlled study that compared five patients treated with midodrine and octreotide with eight patients treated with nonpressor doses of dopamine (35). Notably, midodrine and octreotide were titrated to achieve an increase in MAP by 15 mm Hg. The study showed the superiority of midodrine and octreotide over dopamine, and its use became vastly adopted, likely due to the ease of administration and relatively favorable safety profile. Subsequently, midodrine and octreotide have been shown to be inferior to both terlipressin and norepinephrine (36,37). Therefore, the existing evidence is insufficient to recommend midodrine and octreotide as vasoconstrictor therapy for HRS-1. Current clinical algorithms focus on the augmentation of MAP with the regimen chosen dictated by those that are clinically available (20). It should be noted that in the favorable scenario of HRS-1 reversal, if the pathophysiologic state that predisposed HRS-1 is still present, HRS-1 recurrence may ensue (5%–60%), and retreatment should be pursued as indicated (20).
In patients with hyperbilirubinemia, cholemic nephropathy (also termed cholemic nephrosis, cholemic nephropathy, or bile cast nephropathy) refers to a condition characterized by intratubular bile casts with impaired kidney function in the setting of cholestasis (30). It was originally described in individuals with cholangiocarcinoma or other causes of obstructive jaundice (38). The notion that cholemic nephropathy is implicated in the pathogenesis of HRS-1 was introduced by human autopsy studies reporting a significant proportion of patients with cirrhosis with histologic evidence of intratubular bile casts who had been diagnosed as having HRS-1 premortem (39,40). However, careful consideration is needed when translating animal studies and autopsy results. It remains unclear whether the presence of intratubular bile casts merely reflects reduced GFR and tubular stasis or signifies a potential role in inducing tubular injury (19). Nevertheless, bile acids may pose other effects leading to renal hemodynamic derangements and cardiac output compromise leading to renal hypoperfusion (41). Notably, the presence of renal tubular epithelial cell casts is described in patients with severe hyperbilirubinemia and suggests cholemic tubular injury. However, those casts can be found in the absence of AKI, and hence, their significance remains unclear (42). Finally, greater severity of hyperbilirubinemia has been associated with attenuated response to vasoconstrictors in HRS-1, suggesting that other pathogenic mechanisms might complicate those cases (43). Altogether, the evidence indicates that hyperbilirubinemia itself may independently contribute to the pathogenesis of AKI in cirrhosis, but more studies are needed to answer this question conclusively (Figure 3).
Antimicrobials are frequently prescribed for patients with cirrhosis in the hospital setting. Antibiotics can, therefore, be the cause of AKI either by an allergic reaction leading to acute interstitial nephritis (AIN) or by direct tubular cell toxicity leading to toxic acute tubular injury.
Staphylococcal infections requiring treatment with vancomycin are not uncommon in cirrhosis. Vancomycin is known to cause toxic acute tubular injury in the general population, and it can present clinically as a precipitous rise in serum creatinine (44). Vancomycin nanospheres have been described to precipitate intratubular obstruction, an entity named vancomycin cast nephropathy (45). Currently, studies depicting the risk of vancomycin-associated AKI in patients with cirrhosis are lacking. Nevertheless, patients with decompensated cirrhosis exposed to vancomycin should be cautiously watched for AKI development.
Reports of ciprofloxacin-induced crystal tubulopathy have emerged (46). Although there are no specific reports of this nephrotoxic effect of ciprofloxacin in cirrhosis, these antimicrobials are often prescribed in cirrhosis. Therefore, the possibility of ciprofloxacin-induced tubulopathy should be considered as a potential cause of AKI in this population.
Fluoroquinolones are routinely used for prophylaxis and treatment of spontaneous bacterial peritonitis in patients with decompensated cirrhosis and ascites. Fluoroquinolone-induced AKI secondary to AIN has been reported in the general population (47). Piperacillin, nafcillin, other cephalosporins, and vancomycin can also cause AIN. Similarly, proton pump inhibitors, a common cause of AIN, are also frequently prescribed in cirrhosis (48). However, there is limited literature about the risk of medication-induced AIN in patients with cirrhosis. Nevertheless, the presence of sterile pyuria in a patient exposed to an antibiotic or proton pump inhibitor should alert the practitioner to the possibility of AIN.
Patients with cirrhosis are at considerable risk for acquiring certain glomerulopathies (49). From autopsy and kidney biopsy data, glomerular involvement in cirrhosis is reported to be around 50%, although the majority of cases may only exhibit minor histologic changes without clinical manifestations (49). In a cohort of patients with cirrhosis, examination of kidney specimens by light microscopy and immunofluorescence at autopsy revealed that 61% of patients had IgA nephropathy and 31% had normal parenchyma (50).
Immunoglobulin A Nephropathy.
Hepatic IgA nephropathy is the most common secondary form of IgA nephropathy and the most common type of GN in decompensated cirrhosis, accounting for 50%–90% of the cases (51). The majority of cases of hepatic IgA nephropathy are asymptomatic or manifest slow disease progression (52). It is suggested that defective hepatic processing of IgA secondary to reduced sialo-glycoprotein receptor on hepatocytes in conjunction with portosystemic shunting may cause IgA to deviate from hepatic uptake and depolymerize, subsequently leading to immune complex deposition within the mesangium (52). Management is aimed at supportive strategies with angiotensin-converting enzyme or angiotensin receptor blockers for BP and proteinuria control. Recently, sodium-glucose cotransporter-2 inhibitors have been shown to reduce the risk of progression of CKD in patients with primary IgA nephropathy and albuminuria in a prespecified secondary analysis of the DAPA-CKD trial (53). However, the role of sodium-glucose cotransporter-2 inhibitors in hepatic IgA nephropathy is not known.
Hepatitis C– and Hepatitis B–Associated Glomerulopathies.
With the advent of new antiviral therapies, patients with hepatitis B (HBV) and hepatitis C (HCV) infections are achieving viral suppression and cure, respectively. However, patients can still develop immune-complex GN despite viral suppression as B cell dysregulation may persist (54).
Hepatitis C–Associated Glomerulonephritis.
A glomerular pattern of injury encountered in patients with cirrhosis due to HCV is that of membranoproliferative GN (44). Cryoglobulinemia is often present. Patients can present with nephrotic and nephritic manifestations with impaired kidney function in up to 25% of the cases, often as AKI (44). KDIGO and American Association for the Study of Liver Diseases recommend direct-acting antiviral agents as an initial therapy for HCV-associated GN in patients with stable kidney function and subnephrotic proteinuria (55). In patients who do not respond solely to antivirals, especially in those with cryoglobulinemic features, addition of immunosuppression with rituximab is indicated. Plasma exchange along with immunosuppression may be needed for cryoglobulinemic flares with nephrotic syndrome and/or rapidly progressive GN (45).
Hepatitis B and Glomerulonephritis.
GN associated with HBV can occasionally lead to AKI in cirrhosis. Membranous and membranoproliferative patterns of glomerular injury and type 3 cryoglobulinemia have been reported in association with HBV (56). HBeAg is small and cationic, and it gets deposited in the subepithelial space, precipitating podocyte injury (46). HBsAg and HBcAg are larger in size and anionic with restriction of IgG-HbsAg to the subendothelial space, precipitating endocapillary injury (46). Immunosuppressive agents may accelerate HBV replication and should be avoided in patients with untreated HBV (46). Patients with replicative HBV (HBeAg positivity and/or viral DNA levels of >2000 IU/ml) and GN should receive treatment with nucleoside (lamivudine and entecavir) or nucleotide (tenofovir and adefovir) reverse transcription inhibitors. KDIGO additionally recommends a trial of plasma exchange if cryoglobulin levels >500 mg/dl in patients with symptomatic vasculitis and HBV-associated cryoglobulinemia (57).
Renal Venous Congestion
In decompensated cirrhosis, renal vein congestion as a cause of AKI can be encountered due to abdominal compartment syndrome/intra-abdominal hypertension caused by tense ascites or in congestive heart failure from right ventricular failure from cirrhotic cardiomyopathy and portopulmonary hypertension (58). In compensated cirrhosis, cardiac output is increased to maintain circulatory homeostasis. With disease progression, cirrhotic cardiomyopathy—a state of dysregulated systolic and diastolic function in response to physical stress with no overt left ventricular failure at rest—may develop (59). The pathophysiology relates to impaired β-adrenergic receptor signaling pathways and increased activity of nitric oxide and the endocannabinoid system (60). Large-volume paracentesis to relieve abdominal pressure and renal vein congestion has been reported to increase urine output with a transient rise in GFR in patients with decompensated cirrhosis (19).
Obstructive Acute Tubular Injury
A combination of midodrine, octreotide, and albumin is often used to manage HRS-1. Midodrine has α-adrenergic effects and increases vesical sphincter tone and detrusor-sphincter dyssynergia, leading to a risk of urinary retention and hydroureteronephrosis, particularly in the elderly and those with neurogenic bladder (61). Hence, we recommend vigilance in patients with decompensated cirrhosis who receive midodrine as part of treatment for HRS-1.
Role of Kidney Replacement Therapy in the Management of AKI
The management of patients with AKI and liver disease is dictated by the underlying etiology. With failure of medical management, KRT is considered on a case-by-case basis. For patients who are deemed eligible for liver transplantation, KRT can be offered until kidney function recovers. For patients who are being evaluated for liver transplantation and disposition is not clear, it is reasonable to offer KRT while deciding on the transplantation status. However, for patients who are ineligible for liver transplantation, a multidisciplinary approach, including patients and their families, needs to be considered, weighing the potential risks and benefits. With no signs of AKI reversibility and multiorgan failure in an intensive care setting, offering KRT could be deemed futile (62). Continuous KRT is the modality of choice for hemodynamically unstable patients, whereas intermittent hemodialysis can be attempted in more stable patients (63).
The burden of kidney dysfunction in patients with cirrhosis is rising (1,4). AKI in patients with cirrhosis is not limited to HRS-1. The differential diagnosis includes other cirrhosis-specific causes (e.g., prerenal gastrointestinal losses, cirrhotic cardiomyopathy, portopulmonary-related venous congestion, etc.) and noncirrhosis-specific causes (e.g., medication effect, acute tubular injury, obstructive uropathy, etc.). Management should be tailored according to the cause of AKI (Figure 4). Vasoconstrictor therapy is a specific treatment for those diagnosed with HRS-1. KRT should be offered to patients who fail medical therapy and either are eligible for liver transplantation or have a meaningful chance of kidney recovery or benefit from the intervention.
G. Cullaro reports employment with the University of California, San Francisco and research funding from Mallinckrodt Pharmaceuticals. J.C.Q. Velez reports consultancy agreements with Bayer, Calliditas, Mallinckrodt Pharmaceuticals, and Travere; honoraria from Bayer, Calliditas, Mallinckrodt, Otsuka, and Travere; serving in an advisory or leadership role for the Mallinckrodt Advisory Board and the Travere Advisory Board; and speakers bureau for Otsuka Pharmaceuticals. The remaining author has nothing to disclose.
This study was funded by National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK-026743 (to G. Cullaro).
We thank Serenella A. Velez for drafting some of the illustrations in Figures 1 and 3.
The funding agencies played no role in the analysis of the data or the preparation of this manuscript.
G. Cullaro, S.R. Kanduri, and J.C.Q. Velez conceptualized the study; J.C.Q. Velez was responsible for formal analysis; G. Cullaro, S.R. Kanduri, and J.C.Q. Velez were responsible for methodology; G. Cullaro and J.C.Q. Velez were responsible for project administration; G. Cullaro and J.C.Q. Velez were responsible for visualization; G. Cullaro, S.R. Kanduri, and J.C.Q. Velez wrote the original draft; and G. Cullaro, S.R. Kanduri, and J.C.Q. Velez reviewed and edited the manuscript.
1. Desai AP, Knapp SM, Orman ES, Ghabril MS, Nephew LD, Anderson M, Ginès P, Chalasani NP, Patidar KR: Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis—A US population-based study. J Hepatol 73: 1092–1099, 2020
2. Cullaro G, Verna EC, Lee BP, Lai JC: Chronic kidney disease in liver transplant candidates: A rising burden impacting post-liver transplant outcomes. Liver Transpl 26: 498–506, 2020
3. Belcher JM, Parikh CR, Garcia-Tsao G: Acute kidney injury in patients with cirrhosis: Perils and promise. Clin Gastroenterol Hepatol 11: 1550–1558, 2013
4. Cullaro G, Rubin JB, Fortune BE, Crawford CV, Verna EC, Hsu CY, Liu KD, Brown RS, Lai JC, Rosenblatt R: Association between kidney dysfunction types and mortality among hospitalized patients with cirrhosis. Dig Dis Sci 67: 3426–3435, 2022 10.1007/s10620-021-07159-z
5. Cullaro G, Verna EC, Lai JC: Association between renal function pattern and mortality in patients with cirrhosis. Clin Gastroenterol Hepatol 17: 2364–2370, 2019
6. Bassegoda O, Huelin P, Ariza X, Solé C, Juanola A, Gratacós-Ginès J, Carol M, Graupera I, Pose E, Napoleone L, Albertos S, de Prada G, Cervera M, Fernández J, Fabrellas N, Poch E, Solà E, Ginès P: Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes. J Hepatol 72: 1132–1139, 2020
7. Wong F, Reddy KR, O’Leary JG, Tandon P, Biggins SW, Garcia-Tsao G, Maliakkal BJ, Lai JC, Fallon MB, Vargas HE, Subramanian R, Thuluvath PJ, Kamath PS, Thacker L, Bajaj JS: Impact of chronic kidney disease on outcomes in cirrhosis. Liver Transpl 25: 870–880, 2019
8. Caregaro L, Menon F, Angeli P, Amodio P, Merkel C, Bortoluzzi A, Alberino F, Gatta A: Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 154: 201–205, 1994
9. Francoz C, Nadim MK, Baron A, Prié D, Antoine C, Belghiti J, Valla D, Moreau R, Durand F: Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: Validation of current recommendations. Hepatology 59: 1514–1521, 2014
10. Kalafateli M, Wickham F, Burniston M, Cholongitas E, Theocharidou E, Garcovich M, O’Beirne J, Westbrook R, Leandro G, Burroughs AK, Tsochatzis EA: Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate. Hepatology 65: 582–591, 2017
11. Asrani SK, Jennings LW, Trotter JF, Levitsky J, Nadim MK, Kim WR, Gonzalez SA, Fischbach B, Bahirwani R, Emmett M, Klintmalm G: A model for glomerular filtration rate assessment in liver disease (GRAIL) in the presence of renal dysfunction. Hepatology 69: 1219–1230, 2019
12. Hsu C-Y, Yang W, Parikh RV, Anderson AH, Chen TK, Cohen DL, He J, Mohanty MJ, Lash JP, Mills KT, Muiru AN, Parsa A, Saunders MR, Shafi T, Townsend RR, Waikar SS, Wang J, Wolf M, Tan TC, Feldman HI, Go AS; CRIC Study Investigators: Race, genetic ancestry, and estimating kidney function in CKD. N Engl J Med 385: 1750–1760, 2021
13. Maiwall R, Kumar A, Bhardwaj A, Kumar G, Bhadoria AS, Sarin SK: Cystatin C predicts acute kidney injury and mortality in cirrhotics: A prospective cohort study. Liver Int 38: 654–664, 2018
14. Singapura P, Ma TW, Sarmast N, Gonzalez SA, Durand F, Maiwall R, Nadim MK, Fullinwider J, Saracino G, Francoz C, Sartin R, Trotter JF, Asrani SK: Estimating glomerular filtration rate in cirrhosis using creatinine-based and cystatin C-based equations: Systematic review and meta-analysis. Liver Transpl 27: 1538–1552, 2021
15. Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR: News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document. J Hepatol 71: 811–822, 2019
16. Belcher JM: Acute kidney injury in liver disease: Role of biomarkers. Adv Chronic Kidney Dis 22: 368–375, 2015
17. Leão GS, de Mattos AA, Picon RV, Schacher FC, John Neto G, Jotz RF, Chiesa T, Bombassaro IZ, Possebon JPP, Coral GP, Tovo CV, de Mattos ÂZ: The prognostic impact of different stages of acute kidney injury in patients with decompensated cirrhosis: A prospective cohort study. Eur J Gastroenterol Hepatol 33[Suppl 1]: e407–e412, 2021
18. Martín-Llahí M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, Solá E, Pereira G, Marinelli M, Pavesi M, Fernández J, Rodés J, Arroyo V, Ginès P: Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 140: 488–496.e4, 2011
19. Velez JCQ: Hepatorenal syndrome type 1: From diagnosis ascertainment to goal-oriented pharmacologic therapy. Kidney360 3: 382–395, 2021
20. Velez JCQ, Therapondos G, Juncos LA: Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 16: 137–155, 2020
21. Bonnel AR, Bunchorntavakul C, Reddy KR: Immune dysfunction and infections in patients with cirrhosis. Clin Gastroenterol Hepatol 9: 727–738, 2011
22. Varghese V, Rivera MS, Alalwan A, Alghamdi AM, Ramanand A, Khan SM, Najul-Seda JE, Velez JCQ: Concomitant identification of muddy brown granular casts and low fractional excretion of urinary sodium in AKI. Kidney360 3: 627–635, 2022
23. Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, Gonzalez SA, Mumtaz K, Lim N, Simonetto DA, Sharma P, Sanyal AJ, Mayo MJ, Frederick RT, Escalante S, Jamil K; CONFIRM Study Investigators: Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med 384: 818–828, 2021
24. China L, Freemantle N, Forrest E, Kallis Y, Ryder SD, Wright G, Portal AJ, Becares Salles N, Gilroy DW, O’Brien A; ATTIRE Trial Investigators: A randomized trial of albumin infusions in hospitalized patients with cirrhosis. N Engl J Med 384: 808–817, 2021
25. Velez JCQ, Petkovich B, Karakala N, Huggins JT: Point-of-care echocardiography unveils misclassification of acute kidney injury as hepatorenal syndrome. Am J Nephrol 50: 204–211, 2019
26. Wong F, O’Leary JG, Reddy KR, Garcia-Tsao G, Fallon MB, Biggins SW, Subramanian RM, Thuluvath PJ, Kamath PS, Patton H, Maliakkal B, Tandon P, Vargas H, Thacker L, Bajaj JS: Acute kidney injury in cirrhosis: Baseline serum creatinine predicts patient outcomes. Am J Gastroenterol 112: 1103–1110, 2017
27. Tsien CD, Rabie R, Wong F: Acute kidney injury in decompensated cirrhosis. Gut 62: 131–137, 2013
28. Hernaez R, Solà E, Moreau R, Ginès P: Acute-on-chronic liver failure: An update. Gut 66: 541–553, 2017
29. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano G, Guevara M, Ginès P, Rodés J: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341: 403–409, 1999
30. Velez JCQ, Nietert PJ: Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: A pooled analysis of clinical trials. Am J Kidney Dis 58: 928–938, 2011
31. Velez JCQ, Kadian M, Taburyanskaya M, Bohm NM, Delay TA, Karakala N, Rockey DC, Nietert PJ, Goodwin AJ, Whelan TP: Hepatorenal acute kidney injury and the importance of raising mean arterial pressure. Nephron 131: 191–201, 2015
32. Garcia-Tsao G: Terlipressin and intravenous albumin in advanced cirrhosis—Friend and foe. N Engl J Med 384: 869–871, 2021
33. Eisenman A, Armali Z, Enat R, Bankir L, Baruch Y: Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure. J Intern Med 246: 183–190, 1999
34. Evrard P, Ruedin P, Installé E, Suter PM: Low-dose ornipressin improves renal function in the hepatorenal syndrome. Crit Care Med 22: 363–366, 1994
35. Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A: Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 29: 1690–1697, 1999
36. El-Desoki Mahmoud EI, Abdelaziz DH, Abd-Elsalam S, Mansour NO: Norepinephrine is more effective than midodrine/octreotide in patients with hepatorenal syndrome-acute kidney injury: A randomized controlled trial. Front Pharmacol 12: 675948, 2021
37. Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, Bernardi M, Romanelli RG, Colletta C, Salinas F, Di Giacomo A, Ridola L, Fornasiere E, Caraceni P, Morando F, Piano S, Gatta A, Angeli P; Italian Association for the Study of the Liver Study Group on Hepatorenal Syndrome: Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology 62: 567–574, 2015
38. Mair RD, Lee S, Plummer NS, Sirich TL, Meyer TW: Impaired tubular secretion of organic solutes in advanced chronic kidney disease. J Am Soc Nephrol 32: 2877–2884, 2021
39. Foshat M, Ruff HM, Fischer WG, Beach RE, Fowler MR, Ju H, Aronson JF, Afrouzian M: Bile cast nephropathy in cirrhotic patients: Effects of chronic hyperbilirubinemia. Am J Clin Pathol 147: 525–535, 2017
40. van Slambrouck CM, Salem F, Meehan SM, Chang A: Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int 84: 192–197, 2013
41. Voiosu A, Wiese S, Voiosu T, Bendtsen F, Møller S: Bile acids and cardiovascular function in cirrhosis. Liver Int 37: 1420–1430, 2017
42. Poloni JAT, Perazella MA, Keitel E, Marroni CA, Leite SB, Rotta LN: Utility of a urine sediment score in hyperbilirubinemia/hyperbilirubinuria. Clin Nephrol 92: 141–150, 2019
43. Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, Marinelli M, Solá E, Baccaro ME, Terra C, Arroyo V, Ginès P: Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 51: 219–226, 2010
44. Velez JCQ, Obadan NO, Kaushal A, Alzubaidi M, Bhasin B, Sachdev SH, Karakala N, Arthur JM, Nesbit RM, Phadke GM: Vancomycin-associated acute kidney injury with a steep rise in serum creatinine. Nephron 139: 131–142, 2018
45. Luque Y, Louis K, Jouanneau C, Placier S, Esteve E, Bazin D, Rondeau E, Letavernier E, Wolfromm A, Gosset C, Boueilh A, Burbach M, Frère P, Verpont MC, Vandermeersch S, Langui D, Daudon M, Frochot V, Mesnard L: Vancomycin-associated cast nephropathy. J Am Soc Nephrol 28: 1723–1728, 2017
46. Goli R, Mukku KK, Raju SB, Uppin MS: Acute ciprofloxacin-induced crystal nephropathy with granulomatous interstitial nephritis. Indian J Nephrol 27: 231–233, 2017
47. Hajji M, Jebali H, Mrad A, Blel Y, Brahmi N, Kheder R, Beji S, Fatma LB, Smaoui W, Krid M, Hmida FB, Rais L, Zouaghi MK: Nephrotoxicity of ciprofloxacin: Five cases and a review of the literature. Drug Saf Case Rep 5: 17, 2018
48. Mahmud N, Serper M, Taddei TH, Kaplan DE: The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: A Veterans Affairs cohort study. Gastroenterology 163: 257–269.e6, 2022 10.1053/j.gastro.2022.03.052
49. Newell GC: Cirrhotic glomerulonephritis: Incidence, morphology, clinical features, and pathogenesis. Am J Kidney Dis 9: 183–190, 1987
50. Skogh T, Blomhoff R, Eskild W, Berg T: Hepatic uptake of circulating IgG immune complexes. Immunology 55: 585–594, 1985
51. Pouria S, Feehally J: Glomerular IgA deposition in liver disease. Nephrol Dial Transplant 14: 2279–2282, 1999
52. Nakamoto Y, Iida H, Kobayashi K, Dohi K, Kida H, Hattori N, Takeuchi J: Hepatic glomerulonephritis. Characteristics of hepatic IgA glomerulonephritis as the major part. Virchows Arch A Pathol Anat Histol 392: 45–54, 1981
53. Wheeler DC, Toto RD, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, McMurray JJV, Pecoits-Filho R, Correa-Rotter R, Rossing P, Sjöström CD, Umanath K, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators: A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 100: 215–224, 2021
54. Kupin WL: Viral-associated GN: Hepatitis B and other viral infections. Clin J Am Soc Nephrol 12: 1529–1533, 2017
55. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY, Thadhani R, Chung RT: Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology 63: 408–417, 2016
56. Li SJ, Xu ST, Chen HP, Zhang MC, Xu F, Cheng SQ, Liu ZH: Clinical and morphologic spectrum of renal involvement in patients with HBV-associated cryoglobulinaemia. Nephrology (Carlton) 22: 449–455, 2017
57. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DRW, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JF, Sethi S, Suzuki Y, Tang SCW, Tesar V, Vivarelli M, Wetzels JFM, Lytvyn L, Craig JC, Tunnicliffe DJ, Howell M, Tonelli MA, Cheung M, Earley A, Floege J: Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 100: 753–779, 2021
58. Patel DM, Connor Jr. MJ: Intra-abdominal hypertension and abdominal compartment syndrome: An underappreciated cause of acute kidney injury. Adv Chronic Kidney Dis 23: 160–166, 2016
59. Wiese S, Hove JD, Bendtsen F, Møller S: Cirrhotic cardiomyopathy: Pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol 11: 177–186, 2014
60. Kazory A, Ronco C: Hepatorenal syndrome or hepatocardiorenal syndrome: Revisiting basic concepts in view of emerging data. Cardiorenal Med 9: 1–7, 2019
61. Vaidyanathan S, Soni BM, Hughes PL: Midodrine: Insidious development of urologic adverse effects in patients with spinal cord injury: A report of 2 cases. Adv Ther 24: 712–720, 2007
62. Velez JCQ: Patients with hepatorenal syndrome should be dialyzed? PRO. Kidney360 2: 406–409, 2020
63. Kovvuru K, Velez JCQ: Kidney replacement therapy in patients with acute liver failure and end-stage cirrhosis awaiting liver transplantation. Clin Liver Dis 26: 245–253, 2022
64. Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, Graupera I, Ariza X, Pereira G, Alfaro I, Cárdenas A, Fernández J, Poch E, Ginès P: A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 59: 474–481, 2013
65. Belcher JM, Sanyal AJ, Peixoto AJ, Perazella MA, Lim J, Thiessen-Philbrook H, Ansari N, Coca SG, Garcia-Tsao G, Parikh CR; TRIBE-AKI Consortium: Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 60: 622–632, 2014
66. Allegretti AS, Solà E, Ginès P: Clinical application of kidney biomarkers in cirrhosis. Am J Kidney Dis 76: 710–719, 2020
67. Verna EC, Brown RS, Farrand E, Pichardo EM, Forster CS, Sola-Del Valle DA, Adkins SH, Sise ME, Oliver JA, Radhakrishnan J, Barasch JM, Nickolas TL: Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig Dis Sci 57: 2362–2370, 2012
68. Liu C-W, Huang CC, Tsai HC, Su YB, Huang SF, Lee KC, Hsieh YC, Li TH, Tsai CY, Chong LW, Ou SM, Yang YY, Fan WC, Hou MC, Lin HC, Lee SD: Serum adrenomedullin and urinary thromboxane B2
help early categorizing of acute kidney injury in decompensated cirrhotic patients: A prospective cohort study. Hepatol Res 48: E9–E21, 2018
69. Watany MM, Hagag RY, Okda HI: Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: A pilot study. Clin Chem Lab Med 56: 739–747, 2018
70. Zhang CC, Hoffelt DAA, Merle U: Urinary cell cycle arrest biomarker [TIMP-2]·[IGFBP7] in patients with hepatorenal syndrome. Biomarkers 24: 692–699, 2019