Abstract: Renal dysfunction frequently develops in patients with advanced liver disease. Renal dysfunction in this setting is associated with adverse outcomes and an unfavorable prognosis. Hepatorenal syndrome (HRS), defined as worsening renal function in patients with advanced cirrhosis that can present either acutely (<3 months) or more indolently in the absence of other etiologies, remains a common cause of acute kidney injury. If reversal is not promptly achieved, rapid decline to mortality is common. Volume expansion and vasoconstrictors are the mainstays of therapy. Terlipressin, a vasopressin analogue licensed in several countries but not in the United States, is currently used for the treatment of HRS. Timely liver transplantation remains the only effective therapeutic option for a large group of patients with persistent renal dysfunction despite pharmacotherapy. In patients with underlying chronic renal dysfunction, simultaneous liver-kidney transplantation should be considered. The aim of this article is to present an overview of renal dysfunction in patients with cirrhosis, including diagnosis and management.
The development of renal dysfunction in patients with decompensated cirrhosis was initially recognized in the 19th century.1 Renal dysfunction is a frequent occurrence that is implicated in poor outcomes,2 including increased mortality prior to liver transplantation (LT) as well as higher rates of primary graft nonfunction and inferior graft and patient survival rates post-LT.2
Serum creatinine (sCr) has been included as a prognostic factor for renal dysfunction in patients with cirrhosis in the Model for End-Stage Liver Disease (MELD) score. The MELD score is the scoring system adopted in the United States and elsewhere as the basis for organ allocation in LT. Individual variables of the MELD score have independent weight (an important difference from prior prognostic scores such as the Child-Turcotte-Pugh score), with sCr having more than twice the weight than bilirubin.3 As a consequence of widespread MELD use, the number of patients with renal dysfunction undergoing LT increased from 26.1% in 2002 (pre-MELD) to 29.8% in 2008 (post-MELD).4
Acute and chronic renal dysfunction occur more commonly in patients with cirrhosis than in the general population, with the prevalence of renal disease increasing with severity of liver disease.5 Acute kidney injury (AKI) complicates the course of up to 70% of patients with cirrhosis who are hospitalized for other complications of liver disease. In comparison, the incidence of AKI is 23% in all hospitalized adults6 and 60% in all patients admitted to intensive care.7
AKI is a frequent complication of concurrent clinical events in patients with cirrhosis, including decompensation requiring intensive care support (40%-49%), spontaneous bacterial peritonitis (SBP) (34%), bacterial infections other than SBP (27%), and acute upper gastrointestinal bleeding (11%).8,9 In-hospital mortality associated with AKI is also significantly higher in patients with cirrhosis, particularly in those with concomitant systemic inflammatory response syndrome, compared with those without liver disease (50%-68% vs 9%-11%, respectively).6,10,11 Further deterioration in renal function is also frequent in hospitalized patients with cirrhosis and concomitant chronic kidney disease (CKD).12 The aim of this article is to present an overview of renal dysfunction in patients with cirrhosis, including diagnosis and management.
Diagnosis of Renal Dysfunction
Assessing Renal Function in Patients With Cirrhosis
sCr has important limitations as a marker of renal function in patients with cirrhosis. Sarcopenia and increased tubular secretion of creatinine result in spuriously low sCr levels, potentially overestimating renal function. Hyperbilirubinemia may interfere with measurement of sCr in some assays as well. Blood urea nitrogen concentration is even less reliable because it is affected by dietary protein intake and gastrointestinal bleeding.13 Similar to what has been seen in the general population, sCr levels in patients with cirrhosis are lower in women than men. This physiologic variation is not accounted by the MELD score and can result in sex disparities in LT and increased waitlist mortality.14 Commonly used formulas, such as the Modification of Diet in Renal Disease, CKD-Epidemiology Collaboration, and the Cockroft-Gault formula, also overestimate renal function in patients with cirrhosis.15
An absolute change in sCr concentration of 0.3 mg/dL is considered diagnostic for AKI, supported by the fact that even minor fluctuations in sCr concentration have been associated with adverse outcomes in retrospective studies.16,17 Early AKI can be difficult to recognize during its initial critical hours, as sCr concentration achieves its peak level 48 to 72 hours after kidney injury. This delay can perpetuate exposure to nephrotoxic agents, thus causing further damage. Additionally, kidney injury can occur in the absence of increasing sCr concentration, representing an emerging condition called subclinical AKI.18
Renal Biomarkers
Although accurate markers of glomerular filtration rate (GFR) exist, their availability in clinical practice is limited. Cystatin C is a low-molecular-weight protein that is unaffected by sex, inflammation, or malignancy.19 It is freely filtered by glomeruli and reabsorbed completely by proximal tubular cells without tubular secretion, with fluctuation in urinary levels being mainly due to decreased reabsorption from injured or dysfunctional tubules.19 In patients with cirrhosis and ascites, cystatin C has been valuable in the assessment of renal function as well as a predictor of hepatorenal syndrome (HRS) and mortality.20
Some biomarkers of tubular injury have use in differentiating the etiology of renal dysfunction in patients with cirrhosis. Urinary neutrophil gelatinase-associated lipocalin is expressed in the kidney and induced by injured epithelia. It is higher in acute tubular necrosis (ATN) compared with prerenal azotemia due to volume depletion, CKD, and HRS.21,22 Furthermore, urinary neutrophil gelatinase-associated lipocalin may predict short-term mortality in hospitalized patients with cirrhosis.23
Kidney injury molecule-1 is an apical transmembrane glycoprotein located in proximal tubules and is increased during ischemia.24,25 Higher urinary levels of kidney injury molecule-1 can be found in patients with cirrhosis and ATN and are associated with AKI progression and increased incidence of mortality.26,27
Interleukin-18 and liver-type fatty acid binding protein are other biomarkers that also have been studied in patients with cirrhosis and renal dysfunction26; however, none of these newer tests are routinely available in clinical practice.
Acute Vs Chronic Renal Dysfunction
The most recent guidelines from Kidney Disease Improving Global Outcomes (KDIGO) define acute kidney disease (AKD) as either a GFR of less than 60 mL/min/1.73 m2, a decrease in GFR by 35% or greater or an increase in sCr level by greater than 50%, or structural kidney damage for less than 3 months. The suggested definition of AKI by KDIGO, subsequently modified by the International Club of Ascites, describes it as an increase in sCr of 0.3 mg/dL or more within 48 hours or an increase in sCr to 1.5 or more times baseline within 7 days.28 AKI is further classified into 3 stages (Table 1), and distinguishing between stages 1-A and 1-B may offer additional prognostic information, given higher mortality for patients with stage 1-B disease.29-31 On the other hand, CKD is defined as diminished renal function for 3 or more months, irrespective of the etiology, and is classified into 5 stages depending on GFR.32
HRS is defined as renal dysfunction in patients with cirrhosis in the absence of an alternative etiology. The current suggestion from the International Club of Ascites is that HRS should be considered a specific phenotype of renal dysfunction occurring in patients with decompensated cirrhosis. Definitions of HRS subtypes were updated to reflect whether renal dysfunction is acute, subacute, or chronic. HRS type 1 and type 2 were renamed HRS-AKI and HRS–non-AKI (NAKI), respectively. The diagnosis of HRS-NAKI is made when CKD (HRS-CKD) is present or if subacute kidney disease (HRS-AKD) is recognized, with the latter defined as a renal dysfunction that does not meet criteria for AKI and lasts less than 90 days.33,34 The most recent diagnostic criteria for HRS-AKI are summarized in Table 2.
HRS‐AKI ensues following intense renal vasoconstriction, with marked reduction in renal blood flow and GFR. This occurs in response to splanchnic arterial vasodilation (typical of portal hypertension) with activation of compensatory vasoconstriction. HRS is a diagnosis of exclusion and is difficult to differentiate from ATN, as both HRS and ATN frequently manifest in critically ill patients with cirrhosis. In this population, the prevalence of HRS-AKI ranges from 15% to 43% and is slightly more frequent than ATN (14%-35%) as a cause for AKI.35 HRS is more common in the systemic inflammatory state,36 with a median survival of 2 weeks for patients with HRS-AKI and 4 to 6 months for those with HRS-CKD.37
Pathophysiology
Renal dysfunction in patients with cirrhosis can be separated into 2 broad categories based on the underlying pathophysiology, reflecting either the circulatory disturbance characteristic of decompensated cirrhosis (eg, HRS), or hemodynamic derangements and intrinsic injury to the kidney (eg, glomerulopathies, drug-induced nephrotoxicity). Prerenal azotemia is caused by decreased renal perfusion and is the most common cause of AKI in the general population. In patients with cirrhosis, hypovolemia and/or infection can result in renal hypoperfusion without underlying glomerular injury.11 Decompensated cirrhosis is accompanied by marked splanchnic vasodilation mediated by endogenous vasodilators such as nitric oxide, carbon monoxide, endogenous cannabinoids, and, potentially, bacterial translocation and increased production of proinflammatory cytokines (ie, tumor necrosis factor–α and interleukin-6).38,39
Vasodilation results in decreased effective arterial blood volume and renal hypoperfusion, activating the renin-angiotensin system. This, in turn, induces non-osmotic hypersecretion of antidiuretic hormone, causing intrarenal vasoconstriction.40 Exacerbation of renal hypoperfusion ensues, triggering sodium and free-water retention. Intercurrent events, such as hypovolemia (eg, variceal hemorrhage or excessive diuresis) or further vasodilation precipitated by infections or decreased prostaglandin synthesis due to nonsteroidal anti-inflammatory drugs, can further disturb the delicate compensatory hemodynamic balance in patients with cirrhosis, leading to a rapid decline of renal function.34
The prevalence of metabolic-associated fatty liver disease (MAFLD) has increased steadily in the United States and elsewhere. Worldwide, MAFLD has a prevalence of 25% and is closely related to other important metabolic factors, such as central obesity, insulin resistance, arterial hypertension, and hypertriglyceridemia,41 some of which are independent risk factors of renal dysfunction.42
The prevalence of MAFLD ranges from approximately 55% to 70% in patients with diabetes,43,44 independently increasing the risk of complications such as retinopathy and CKD.45,46 Even though type 2 diabetes mellitus and hypertension are responsible for more than 70% of cases of CKD in Western populations, recent data suggest that MAFLD per se may be a risk factor of decreased renal function.47 In patients with MAFLD, the prevalence of CKD ranges from 20% to 55% compared with 5% to 30% among those without MAFLD and after adjusting for other independent risk factors of CKD.42,46,48,49 The severity of MAFLD correlates with the stage of CKD.50 Potential mechanisms may include activation of the renin-angiotensin system, proinflammatory cytokines, and oxidative stress.
An association exists between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and glomerulo-pathies and vasculitides.51 The frequency of HBV-related renal disease is higher in endemic areas and HBV-infected children.52 Manifestations include membranous nephropathy, membranoproliferative glomerulonephritis, and polyarteritis nodosa as well as mesangial proliferative glomerulonephritis, immunoglobulin (Ig) A nephropathy, focal segmental glomerulosclerosis, minimal change disease, and amyloidosis. Membranous nephropathy, the most common association, typically presents with proteinuria and is characterized by deposition of immune complexes in the subepithelial glomerular basement membrane.
HCV infection also is implicated in renal dysfunction, with HCV seropositivity being associated with a nearly 3-fold higher risk of end-stage renal disease in patients with preexisting renal dysfunction (estimated GFR ≤30) from other causes.53,54 HCV may impact renal function by causing immune-mediated injury and through direct effects of the virus on the kidney.55 Renal dysfunction associated with HCV can manifest as membranoproliferative glomerulonephritis, membranous nephropathy, and focal segmental glomerulosclerosis. Type I membranoproliferative glomerulonephritis associated with type 2 mixed cryoglobulinemia is the most common HCV-associated glomerulopathy. Common features include proteinuria, microscopic hematuria, hypertension, acute nephritis, and nephrotic syndrome.56
Alcohol-related cirrhosis is associated with an altered IgA metabolism in which IgA deposition in the glomerular mesangium can lead to clinically overt IgA nephropathy, progressing to CKD and adversely affecting prognosis. However, the IgA1 of alcohol-related cirrhosis has a modified N-glycosylation that is not found in primary IgA nephropathy.57 This condition may present with microscopic or gross hematuria and proteinuria ranging from mild to nephrotic.58 Alcohol-related cirrhosis with AKI is associated with high mortality, irrespective of the etiology of renal dysfunction, with no difference in survival noted between patients with HRS and those with ATN.59
Management
Renal dysfunction in patients with cirrhosis is a complex condition in which factors such as severity of underlying liver disease, evolution of renal dysfunction, and presence of other comorbid conditions are intertwined and heavily influence outcomes. Prompt identification of potential causes of renal dysfunction, particularly when acute, permits implementation of specific interventions that may mitigate its clinical course (Table 3).
Volume Expansion
Diuretics should be immediately discontinued upon recognition of AKI in patients with cirrhosis. Cautious expansion of intravascular volume is recommended, with the type of fluid used dictated by the putative etiology of AKI. Crystalloids are inexpensive, widely available, and preferred for patients with volume depletion due to diarrhea or excessive diuresis. Currently, accepted indications for intravenous albumin include prevention of circulatory dysfunction following large-volume paracentesis, prevention of HRS in patients with SBP, and management of HRS in association with vasoconstrictor drugs.31 Albumin accounts for approximately 75% of plasma oncotic pressure, with evidence supporting its use as a plasma expander in patients with cirrhosis. Albumin also has modest immune-modulating and antioxidant properties.60-62
Albumin improves effective blood volume by several mechanisms, including attenuation of peripheral arterial vasodilation and endothelial dysfunction, thus enhancing cardiac work (effects that are not achieved by other colloids)63 and increasing arterial pressure in patients with HRS treated with terlipressin (effects not observed with terlipressin alone).64 Albumin improves cardiac inotropism in animal models by reversing the negative effects of tumor necrosis factor–α and oxidative stress on cardiac contractility.65
Vasoconstrictors
The combination of intravenous albumin and vasoconstrictors reduces short-term mortality in patients with HRS-AKI compared with albumin alone.66 Vasoconstrictors should be reserved for patients with at least AKI stage 1-B (sCr ≥1.5 mg/dL) due to concerns about early use of these drugs and lack of data supporting their use in patients with HRS and lower sCr.33 The choice of vasoconstrictor depends on availability of these agents, familiarity, and the level of care. Midodrine and octreotide are commonly used in general medical units, whereas norepinephrine infusion requires intensive care monitoring and central venous access. Albumin in combination with norepinephrine may be superior to albumin plus midodrine and octreotide in reversing HRS-AKI.66
The vasopressin analogue terlipressin is currently licensed in many countries but not in the United States. Data from a phase 3, multicenter, randomized, double-blind, placebo-controlled trial showed that terlipressin administered as an intravenous bolus of 1 to 2 mg every 6 hours plus albumin was more effective than placebo plus albumin in improving renal function in patients with HRS-AKI.67 Terlipressin was also more effective in reversing HRS-AKI when used in combination with albumin compared with the combination of midodrine and octreotide.68 Initially introduced to counteract splanchnic arterial vasodilation and thus reduce portal hypertension, as well as to improve reduced effective circulating volume,69 terlipressin with albumin is most commonly used in the treatment of HRS in countries where it is available.70
The use of terlipressin was initially associated with a high incidence of adverse events, ranging from approximately 30% to 90% in different studies.71,72 The use of a continuous infusion of terlipressin was subsequently explored, allowing for lower doses and fewer side effects. A multicenter, controlled clinical trial that evaluated whether continuous intravenous infusion of terlipressin is comparable to bolus found no significant difference in terms of response; however, the rate of adverse events—including serious adverse events—was lower among study participants allocated to continuous infusion compared with those allocated to bolus (35.3% vs 62.2%).73 Findings from a recent large, North American, multicenter, randomized, placebo-controlled, double-blind phase 3 trial demonstrated a significant benefit for reversal of renal dysfunction in patients with cirrhosis treated with terlipressin plus albumin compared with those treated with albumin alone. This response was durable and associated with less need for early renal replacement therapy (RRT).74
In patients with acute-on-chronic liver failure, the pathophysiology of renal dysfunction may be different than in patients with decompensated cirrhosis. Acute-on-chronic liver failure is characterized by a cytokine storm that results in circulatory dysfunction and organ failure, with a high incidence of AKI with poor response to vasoconstrictors.75 A recent open-label, noninferiority, randomized, controlled trial that evaluated the efficacy of noradrenaline vs terlipressin for reversal of HRS-AKI in patients with acute-on-chronic liver failure found that early, complete response at days 4 and 7 was significantly higher with terlipressin than with noradrenaline (18.3% vs 0% and 35.0% vs 8.3%, respectively). Similarly, reversal of renal dysfunction at 14 days was also higher in patients treated with terlipressin than in those allocated to norepinephrine (40.0% vs 16.7%, respectively). Patients who had received terlipressin required less RRT and had higher survival rates (40% vs 20%).76
Terlipressin has also been studied in the outpatient setting as a bridge to LT and for management of refractory ascites in patients with cirrhosis and AKI who do not meet the criteria for HRS-AKI.77,78 Results from a 23-patient case series found that ambulatory (outpatient) continuous intravenous terlipressin infusion was not associated with severe adverse events, suggesting that it may reduce the frequency of large-volume paracentesis and the need for hospitalization in carefully selected patients.79
A systemic review analyzed 12 studies published between 1997 and 2016 that explored the efficacy of terlipressin in improving ascites or preventing paracentesis-induced circulatory dysfunction. Terlipressin had a beneficial hemodynamic effect in nonrefractory ascites by increasing mean arterial pressure and systemic vascular resistance and by decreasing heart rate and cardiac output, thus increasing central blood volume; however, the results did not support the efficacy of terlipressin for preventing AKI in patients with ascites.80
LT candidates with HRS-AKI treated with terlipressin and albumin have improved renal outcomes posttransplantation. One study showed that response to treatment resulted in decreased need for RRT post-LT and lower risk of CKD at 1 year post-LT; however, no significant survival benefit was noted.81
HRS-CKD is characterized by a high recurrence rate after withdrawal of pharmacologic treatment, and the role of terlipressin in this setting is less well defined. Results from one study showed that 19 of 31 patients with HRS-CKD (61%) responded to treatment with terlipressin and albumin, but 11 responders (58%) relapsed after withdrawal of therapy. No significant differences regarding development of AKI, need for RRT, frequency of CKD at 1 year post-LT, length of hospitalization, or survival were noted between responders and nonresponders.82 These findings were subsequently corroborated by another study that showed a 50% recurrence of HRS-CKD compared with 8% for HRS-AKI following cessation of treatment with terlipressin and albumin.83
Renal Replacement Therapy
Approximately 30% of patients with cirrhosis hospitalized with AKI will require RRT.84 RRT may be considered for select patients with HRS-AKI who fail to respond to medical therapy and are candidates for LT as a bridge to either isolated LT or simultaneous liver-kidney transplantation (SLKT), or for those expected to recover from a reversible form of liver injury. Hypotension frequently develops during intermittent hemodialysis in patients with cirrhosis; therefore, continuous veno-venous hemodialysis is the preferred modality. RRT in patients with cirrhosis also is associated with increased risks of cardiac events and complications related to vascular access.85 Peritoneal dialysis carries a higher risk of infection, which can jeopardize candidacy for LT.
Transjugular Intrahepatic Portosystemic Shunt
Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) may increase GFR in patients with HRS86; however, the benefit is short-lived, particularly in HRS-AKI. Improvement in renal function within 2 weeks of the procedure has been observed in patients with either HRS-AKI or HRS-CKD, along with increased urinary sodium excretion and amelioration of ascites. Survival at 1 year post-TIPS is close to 40%, but approximately 25% of patients show no improvement of renal function.87 TIPS is contraindicated in severe hepatocellular dysfunction,88 which is commonly encountered in patients with HRS-AKI.
Prognosis
Renal dysfunction in patients with cirrhosis is associated with increased mortality, with survival rates showing a striking variation depending on the etiology.89-91 HRS-AKI is associated with the worst short-term median survival in the absence of LT (1 month), and although HRS-CKD follows a more protracted clinical course, it is also associated with poor median survival (6 months).92 The optimal cutoff for the MELD score to predict 3-month survival in patients with HRS appears to be 20; median survival is 34 weeks for MELD scores lower than 20 vs 4 weeks for MELD scores 20 or higher.39 Restoration of hepatic function following LT is associated with resolution of HRS-AKI in the majority of patients (76%). The duration of RRT pretransplantation appears to be the only reliable predictive factor for nonreversal of HRS in patients undergoing LT, with a 6% increased risk of nonreversal with each additional day on dialysis.93
Similar to the general population, ATN in patients with cirrhosis is indicative of various renal insults and is associated with a higher 6-month mortality in patients with cirrhosis not undergoing LT.85 The mortality rates have been determined to be 85% for patients not listed for LT, 52% for patients listed for LT but not transplanted, 34% for patients who have undergone LT, and 12% for patients who have undergone SLKT.
Preexisting renal dysfunction in patients with cirrhosis is an independent predictor of increased mortality post-LT and has been associated with adverse outcomes such as increased length of intensive care stays and higher rates of AKI requiring RRT.2,94,95 However, the severity of renal dysfunction and short-term (<4 weeks) need for RRT prior to LT have no impact on 1-year mortality.96 In patients with cirrhosis and AKI who are ineligible for LT, short-term mortality is close to 90%, and, therefore, RRT is often futile in this setting.97
Simultaneous Liver-Kidney Transplantation
LT recipients with CKD are at higher risk for liver graft failure and mortality, particularly if they require RRT, compared with those with preserved renal function.98 End-stage renal disease occurs in 5% to 10% of LT recipients within the first year posttransplantation, but only approximately 1% of kidney transplantations (KTs) in the United States are performed for patients who had previously undergone isolated LT.99 SLKT has steadily increased in the United States in the past decade, from 2.6% to 7.1%.100 This increase reflects several factors, such as poor outcomes in LT recipients with renal dysfunction, inability to predict which candidates will develop worsening renal dysfunction post-LT, and absence of a mechanism to expedite KT in LT recipients in whom advanced CKD develops.101 To standardize criteria for SLKT across the country, the United Network for Organ Sharing enacted policies to address eligibility criteria for SLKT and adjust the prioritization of LT recipients in whom renal dysfunction develops, thereby providing a safety net for these patients.102 Duration of RRT for more than 90 days and age older than 60 years are associated with poor outcomes following LT alone, indicating that SLKT should be considered over LT in this population.103 The current criteria for SLKT are summarized in Table 4.
Advantages of SLKT include not only shorter waiting times for KT (in the absence of a living donor, the average waiting time for a deceased donor KT is >5 years), but also improved immunologic outcomes, as implantation of 2 organs from different donors is avoided along with the consequent complications that might ensue from human leukocyte antigen tissue typing and compatibility, which can be more significant in KT than LT.101 The liver graft appears to confer an immunologic advantage to the renal graft in SLKT recipients compared with patients undergoing isolated KT, conferring diminished risks of acute cellular rejection and antibody-mediated rejection as well as promoting preservation of long-term renal function.104
The traditional technique for SLKT entails separate implantation of the liver followed by the kidney. An alternative is the recovery of the liver and kidney en bloc, with the donor renal artery anastomosed to the donor splenic artery, resulting in simultaneous reperfusion of both organs after implantation.105 This strategy shortens kidney cold ischemia time, with no adverse impact on 1-year liver or graft survival.
In recent years, the number of HCV-positive organs transplanted to HCV-negative recipients has increased significantly, reflecting the ability to treat HCV infection posttransplantation with direct-acting antiviral agents as well as the increased donor pool consequent to the surge of opioid-related deaths.106 The efficacy and safety of direct-acting antiviral agents posttransplantation have been demonstrated not only in clinical trials but also in real-world cohorts of LT and KT recipients.107,108 Furthermore, emerging data suggest that the use of HCV–positive grafts in HCV-negative recipients is not associated with worse outcomes in SLKT when antiviral therapy is promptly used posttransplantation.109
Conclusion
Regardless of the etiology, renal dysfunction commonly occurs in patients with advanced cirrhosis and is associated with increased mortality and poor outcomes. Clinicians should have a low threshold for diagnosing potentially reversible causes of renal dysfunction and, therefore, have a heightened urgency to avoid renal insults. HRS, particularly HRS-AKI, is associated with extremely poor survival in the absence of LT even after implementation of RRT. Pharmacotherapy is frequently used as a bridge to LT, as renal function often improves once hepatic function is restored following transplantation. Specific criteria have been set to determine eligibility for SLKT and should be followed in clinical practice.
Disclosures
Dr Martin has consulted for Mallinckrodt. The other authors have no relevant conflicts of interest to disclose.
References
1. Schrier R. Diseases of the Kidney and Urinary Tract. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
2. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology. 2002;35(5):1179-1185.
3. Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol. 2005;42(suppl)(1):S100-S107.
4. Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, 1999-2008. Am J Transplant. 2010;10(4 pt 2):1003-1019.
5. Choi YJ, Kim JH, Koo JK, et al. Prevalence of renal dysfunction in patients with cirrhosis according to ADQI-IAC working party proposal. Clin Mol Hepatol. 2014;20(2):185-191.
6. Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35(4):349-355.
7. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411-1423.
8. Cárdenas A, Ginès P, Uriz J, et al. Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology. 2001;34(4 pt 1):671-676.
9. Carvalho GC, Regis CdeA, Kalil JR, et al. Causes of renal failure in patients with decompensated cirrhosis and its impact in hospital mortality. Ann Hepatol. 2012;11(1):90-95.
10. Brown JR, Rezaee ME, Marshall EJ, Matheny ME. Hospital mortality in the United States following acute kidney injury. Biomed Res Int. 2016;2016:4278579.
11. Thabut D, Massard J, Gangloff A, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology. 2007;46(6):1872-1882.
12. Warner NS, Cuthbert JA, Bhore R, Rockey DC. Acute kidney injury and chronic kidney disease in hospitalized patients with cirrhosis. J Investig Med. 2011;59(8):1244-1251.
13. Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis. 2003;41(2):269-278.
14. Mindikoglu AL, Regev A, Seliger SL, Magder LS. Gender disparity in liver transplant waiting-list mortality: the importance of kidney function. Liver Transpl. 2010;16(10):1147-1157.
15. MacAulay J, Thompson K, Kiberd BA, Barnes DC, Peltekian KM. Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: are the equations for estimating renal function better? Can J Gastroenterol. 2006;20(8):521-526.
16. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16(11):3365-3370.
17. Newsome BB, Warnock DG, McClellan WM, et al. Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med. 2008;168(6):609-616.
18. Moledina DG, Parikh CR. Phenotyping of acute kidney injury: beyond serum creatinine. Semin Nephrol. 2018;38(1):3-11.
19. Levey AS, Tighiouart H, Simon AL, Inker LA. Comparing newer GFR estimating equations using creatinine and cystatin C to the CKD-EPI equations in adults. Am J Kidney Dis. 2017;70(4):587-589.
20. Sharawey MA, Shawky EM, Ali LH, Mohammed AA, Hassan HA, Fouad YM. Cystatin C: a predictor of hepatorenal syndrome in patients with liver cirrhosis. Hepatol Int. 2011;5(4):927-933.
21. Fagundes C, Pépin MN, Guevara M, et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol. 2012;57(2):267-273.
22. Jaques DA, Spahr L, Berra G, et al. Biomarkers for acute kidney injury in decompensated cirrhosis: a prospective study. Nephrology (Carlton). 2019;24(2):170-180.
23. Verna EC, Brown RS, Farrand E, et al. Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig Dis Sci. 2012;57(9):2362-2370.
24. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(1):237-244.
25. Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transplant. 2009;24(11):3265-3268.
26. Belcher JM, Sanyal AJ, Peixoto AJ, et al; TRIBE-AKI Consortium. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology. 2014;60(2):622-632.
27. Belcher JM, Garcia-Tsao G, Sanyal AJ, et al; TRIBE-AKI Consortium. Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin J Am Soc Nephrol. 2014;9(11):1857-1867.
28. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 2013;61(5):649-672.
29. Fagundes C, Barreto R, Guevara M, et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol. 2013;59(3):474-481.
30. Huelin P, Piano S, Sola E, et al. Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure. Clin Gastroenterol Hepatol. 2017;15(3):438-445.e5.
31. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-460.
32. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67(6):2089-2100.
33. Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-974.
34. 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. 2019;71(4):811-822.
35. Ginès P, Solà E, Angeli P, Wong F, Nadim MK, Kamath PS. Hepatorenal syndrome. Nat Rev Dis Primers. 2018;4(1):23.
36. Solé C, Solà E, Huelin P, et al. Characterization of inflammatory response in hepatorenal syndrome: relationship with kidney outcome and survival. Liver Int. 2019;39(7):1246-1255.
37. Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet. 2003;362(9398):1819-1827.
38. Martin PY, Ginès P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339(8):533-541.
39. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005;41(3):422-433.
40. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8(5):1151-1157.
41. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.
42. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138-1153.
43. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801.
44. Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30(5):1212-1218.
45. Targher G, Mantovani A, Pichiri I, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care. 2014;37(6):1729-1736.
46. Targher G, Bertolini L, Rodella S, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia. 2008;51(3):444-450.
47. Huh JH, Kim JY, Choi E, Kim JS, Chang Y, Sung KC. The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study. PLoS One. 2017;12(7):e0180951.
48. Pan LL, Zhang HJ, Huang ZF, et al. Intrahepatic triglyceride content is independently associated with chronic kidney disease in obese adults: a cross-sectional study. Metabolism. 2015;64(9):1077-1085.
49. Targher G, Bertolini L, Rodella S, Lippi G, Zoppini G, Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin J Am Soc Nephrol. 2010;5(12):2166-2171.
50. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014;11(7):e1001680.
51. Fabrizi F, Martin P, Messa P. Hepatitis B and hepatitis C virus and chronic kidney disease. Acta Gastroenterol Belg. 2010;73(4):465-471.
52. Levy M, Chen N. Worldwide perspective of hepatitis B-associated glomerulonephritis in the 80s. Kidney Int Suppl. 1991;35:S24-S33.
53. Tsui JI, Vittinghoff E, Shlipak MG, et al. Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease. Arch Intern Med. 2007;167(12):1271-1276.
54. Dalrymple LS, Koepsell T, Sampson J, et al. Hepatitis C virus infection and the prevalence of renal insufficiency. Clin J Am Soc Nephrol. 2007;2(4):715-721.
55. Pol S, Parlati L, Jadoul M. Hepatitis C virus and the kidney. Nat Rev Nephrol. 2019;15(2):73-86.
56. Ozkok A, Yildiz A. Hepatitis C virus associated glomerulopathies. World J Gastroenterol. 2014;20(24):7544-7554.
57. Tissandié E, Morelle W, Berthelot L, et al. Both IgA nephropathy and alcoholic cirrhosis feature abnormally glycosylated IgA1 and soluble CD89-IgA and IgG-IgA complexes: common mechanisms for distinct diseases. Kidney Int. 2011;80(12):1352-1363.
58. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med. 2002;347(10):738-748.
59. Lenhart A, Hussain S, Salgia R. Chances of renal recovery or liver transplantation after hospitalization for alcoholic liver disease requiring dialysis. Dig Dis Sci. 2018;63(10):2800-2809.
60. Fernández J, Clària J, Amorós A, et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology. 2019;157(1):149-162.
61. Arroyo V, García-Martinez R, Salvatella X. Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol. 2014;61(2):396-407.
62. O’Brien AJ, Fullerton JN, Massey KA, et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med. 2014;20(5):518-523.
63. Fernández J, Monteagudo J, Bargallo X, et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology. 2005;42(3):627-634.
64. Ortega R, Ginès P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology. 2002;36(4 pt 1):941-948.
65. Bortoluzzi A, Ceolotto G, Gola E, et al. Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology. 2013;57(1):266-276.
66. Facciorusso A, Chandar AK, Murad MH, et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2017;2(2):94-102.
67. Boyer TD, Sanyal AJ, Wong F, et al; REVERSE Study Investigators. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150(7):1579-1589.e2.
68. Cavallin M, Kamath PS, Merli M, et al; 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. 2015;62(2):567-574.
69. Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol. 2008;48(suppl 1):S93-S103.
70. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53(3):397-417.
71. Sanyal AJ, Boyer T, Garcia-Tsao G, et al; Terlipressin Study Group. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134(5):1360-1368.
72. Martín-Llahí M, Pépin MN, Guevara M, et al; TAHRS Investigators. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134(5):1352-1359.
73. Cavallin M, Piano S, Romano A, et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study. Hepatology. 2016;63(3):983-992.
74. Wong FC, Curry MP, Reddy KR, et al. The CONFIRM study: a North American randomized controlled trial (RCT) of terlipressin plus albumin for the treatment of hepatorenal syndrome type 1 (HRS-1) [abstract LO5]. Hepatology. 2019;70(6).
75. Maiwall R, Kumar S, Chandel SS, et al. AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis. Hepatol Int. 2015;9(4):627-639.
76. Arora V, Maiwall R, Rajan V, et al. Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure. Hepatology. 2020;71(2):600-610.
77. Gow PJ, Ardalan ZS, Vasudevan A, Testro AG, Ye B, Angus PW. Outpatient terlipressin infusion for the treatment of refractory ascites. Am J Gastroenterol. 2016;111(7):1041-1042.
78. Vasudevan A, Ardalan Z, Gow P, Angus P, Testro A. Efficacy of outpatient continuous terlipressin infusions for hepatorenal syndrome. Hepatology. 2016;64(1):316-318.
79. Gow PJ, Sinclair M, Thwaites PA, et al. Safety and efficacy of outpatient continuous terlipressin infusion for the treatment of portal hypertensive complications in cirrhosis [published online September 23, 2020]. Eur J Gastroenterol Hepatol. doi:10.1097/MEG.0000000000001950.
80. Bai Z, An Y, Guo X, et al. Role of terlipressin in cirrhotic patients with ascites and without hepatorenal syndrome: a systematic review of current evidence. Can J Gastroenterol Hepatol. 2020;2020:5106958.
81. Piano S, Gambino C, Vettore E, et al. Response to terlipressin and albumin is associated with improved liver transplant outcomes in patients with hepatorenal syndrome [published online September 1, 2020]. Hepatology. doi:10.1002/hep.31529.
82. Rodriguez E, Henrique Pereira G, Solà E, et al. Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: effects on kidney function and transplantation outcomes. Liver Transpl. 2015;21(11):1347-1354.
83. Nguyen-Tat M, Jäger J, Rey JW, et al. Terlipressin and albumin combination treatment in patients with hepatorenal syndrome type 2. United European Gastroenterol J. 2019;7(4):529-537.
84. Allegretti AS, Ortiz G, Wenger J, et al. Prognosis of acute kidney injury and hepatorenal syndrome in patients with cirrhosis: a prospective cohort study. Int J Nephrol. 2015;2015:108139.
85. Allegretti AS, Parada XV, Eneanya ND, et al. Prognosis of patients with cirrhosis and AKI who initiate RRT. Clin J Am Soc Nephrol. 2018;13(1):16-25.
86. Ochs A, Rössle M, Haag K, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for refractory ascites. N Engl J Med. 1995;332(18):1192-1197.
87. Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut. 2000;47(2):288-295.
88. Copelan A, Kapoor B, Sands M. Transjugular intrahepatic portosystemic shunt: indications, contraindications, and patient work-up. Semin Intervent Radiol. 2014;31(3):235-242.
89. Kupin WL. Viral-associated GN: hepatitis C and HIV. Clin J Am Soc Nephrol. 2017;12(8):1337-1342.
90. Shah AS, Amarapurkar DN. Spectrum of hepatitis B and renal involvement. Liver Int. 2018;38(1):23-32.
91. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361(13):1279-1290.
92. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005;41(6):1282-1289.
93. Wong F, Leung W, Al Beshir M, Marquez M, Renner EL. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transpl. 2015;21(3):300-307.
94. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation. 1995;59(3):361-365.
95. Lafayette RA, Paré G, Schmid CH, King AJ, Rohrer RJ, Nasraway SA. Pretransplant renal dysfunction predicts poorer outcome in liver transplantation. Clin Nephrol. 1997;48(3):159-164.
96. Horvatits T, Pischke S, Proske VM, et al. Outcome and natural course of renal dysfunction in liver transplant recipients with severely impaired kidney function prior to transplantation. United European Gastroenterol J. 2018;6(1):104-111.
97. Simonetto DA, Gines P, Kamath PS. Hepatorenal syndrome: pathophysiology, diagnosis, and management. BMJ. 2020;370:m2687.
98. Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001;72(12):1934-1939.
99. Gonwa TA, McBride MA, Mai ML, Wadei HM. Kidney transplantation after previous liver transplantation: analysis of the organ procurement transplant network database. Transplantation. 2011;92(1):31-35.
100. US Department of Health and Human Services, Health Resources and Services Administration. OPTN/SRTR 2018 annual data report: liver. https://srtr.transplant.hrsa.gov/annual_reports/2018/Liver.aspx#LI_2_char_adult_waiting_clin. Accessed April 6, 2021.
101. Lum EL, Cárdenas A, Martin P, Bunnapradist S. Current status of simultaneous liver-kidney transplantation in the United States. Liver Transpl. 2019;25(5):797-806.
102. Organ Procurement and Transplantation Network. OPTN policies. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed April 6, 2021.
103. Pita A, Kaur N, Emamaullee J, et al. Outcomes of liver transplantation in patients on renal replacement therapy: considerations for simultaneous liver kidney transplantation versus safety net. Transplant Direct. 2019;5(10):e490.
104. Taner T, Heimbach JK, Rosen CB, Nyberg SL, Park WD, Stegall MD. Decreased chronic cellular and antibody-mediated injury in the kidney following simultaneous liver-kidney transplantation. Kidney Int. 2016;89(4):909-917.
105. Lee TC, Cortez AR, Kassam AF, et al. Outcomes of en bloc simultaneous liver-kidney transplantation compared to the traditional technique. Am J Transplant. 2020;20(4):1181-1187.
106. Gonzalez SA, Trotter JF. The rise of the opioid epidemic and hepatitis C-positive organs: a new era in liver transplantation. Hepatology. 2018;67(4):1600-1608.
107. Saxena V, Khungar V, Verna EC, et al. Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: results from the HCV-TARGET study. Hepatology. 2017;66(4):1090-1101.
108. Nookala AU, Crismale J, Schiano T, et al. Direct-acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver-kidney transplant recipients. Clin Transplant. 2018;32(3):e13198.
109. Crismale JF, Khalid M, Bhansali A, et al. Liver, simultaneous liver-kidney, and kidney transplantation from hepatitis C-positive donors in hepatitis C-negative recipients: a single-center study. Clin Transplant. 2020;34(1):e13761.
110. Carrion AF, Radhakrishnan R, Martin P. Diagnosis and management of renal dysfunction in patients with cirrhosis. Expert Rev Gastroenterol Hepatol. 2020;14(1):1-7.