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Acute kidney injury in acute liver failure: a review Expert Rev. Gastroenterol. Hepatol. 7(8), 701–712 (2013)
Joanna K Moore1, Eleanor Love1, Darren G Craig2, Peter C Hayes3 and Kenneth J Simpson*3 1 Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Little France, Edinburgh, EH16 4SA, UK 2 Gastroenterology Department, James Cook University Hospital, South Tees NHS Foundation Trust, Middlesbrough, TS4 3BW, UK 3 Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, EH16 4SA, UK *Author for correspondence: Tel.: +44 131 242 1717 Fax: +44 131 242 1633 [email protected]
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Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review. KEYWORDS: acute kidney injury • acute liver failure • renal biomarkers
Acute (or fulminant) liver failure (ALF) is an uncommon clinical condition. Annual cases reported in the USA are estimated to be approximately 2000 cases per year [1], and in the UK approximately 1–8 cases per million population [2]. There are many causes of ALF, such as drug reactions, viral hepatitis, autoimmunity, acute fatty liver of pregnancy or hemolysis, elevated liver enzymes and low platelets, Wilson’s disease and shock. However, no identifiable cause is reported in up to 15% of cases, so-called non-A–E or seronegative hepatitis [3]. The relative frequency of these different etiologies varies in different parts of the world. In the developing world, the most common cause of ALF is viral infection; by contrast, acetaminophen (paracetamol) overdose is the leading cause in most Western populations [4]. ALF should not be confused with the separate entity of acute-on-chronic liver failure which occurs in cirrhotic patients and is discussed in a separate review in this journal [5]. The presenting clinical features of ALF are non-specific, including anorexia, fatigue, abdominal pain, jaundice and fever before progressing to hepatic encephalopathy (HE) [4]. HE is the cardinal clinical feature differentiating severe liver injury from ALF. As the condition progresses, intracranial pressure (ICP) may increase due to the development of cerebral edema. Coagulation abnormalities are 10.1586/17474124.2013.837264
common, but significant bleeding is relatively rare, explained by the balanced coagulation state recently reported in patients with ALF [6]. Electrolyte disturbances are also common, with hypoglycemia particularly dangerous. Hypotension, peripheral vasodilatation and respiratory failure may precede the development of multiorgan failure and death [4]. Clinical features of the systemic inflammatory response [7] are commonly reported in the absence of infection. However, sepsis is frequently observed and a common mode of death in patients with ALF [8]. General good supportive intensive care has improved the prognosis of patients with ALF. However, emergency liver transplantation is a life-saving procedure in highly selected individuals. Bioartificial liver support has shown some promise [9], usually applied to ‘bridge’ patients to emergency transplantation, but artificial liver support has yet to be translated into general clinical practice. Many patients with ALF develop acute kidney injury (AKI) [10]. The occurrence of AKI in the context of ALF is associated with increased morbidity and mortality. In the UK, deteriorating renal function or elevated serum creatinine (>300 mmol/l) are included in the transplant listing criteria for acetaminopheninduced ALF [11]. However, recovery of renal function is the norm following spontaneous
2013 Informa UK Ltd
ISSN 1747-4124
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survival or emergency liver transplantation [12]. Improved understanding of the pathogenesis of AKI associated with ALF should inform the identification of better biomarkers of renal dysfunction, aid prognostication and potentially the development of novel therapies; these topics are discussed in more detail in this expert review.
criteria that is now generally accepted and widely applied [14]. Although the newer classification added small but important modifications to the definition of AKI, there are few reported differences in the diagnostic or prognostic performance (TABLE 1). A recent working party suggested the definition of AKI in patients with cirrhosis should be expanded to include all causes of acute deterioration in renal function defined as an increase in serum creatinine of >50% from baseline or a rise in serum creatinine >26.4 mmol/l (>0.3 mg/dl) in 0.3 mg/dl (>26.4 mmol/l) or >150–200% of the basal value
6 h
2
Increased serum creatinine >200–300% basal value
12 h
3
Increased serum creatinine >300% basal value, or serum creatinine >4.0 mg/dl (>354 mmol/l) with an acute increase of at least 0.5 mg/dl (44 mmol/l)
500 ml/day is a commonly used criterion for withdrawal of RRT. In a recent review of patients with acetaminophen-induced AKI, recovery of renal function prior to discharge from a tertiary referral center was associated with female gender, lower admission mean arterial blood pressure, day 3 MELD score and AKI stage [12]. Two landmark multicenter randomized controlled trials have been published, designed to examine the question of ‘dosage’ of RRT [58,59]. Researchers compared ‘less intensive’ with ‘intensive’ RRT and neither demonstrated any survival benefit with continuous RRT doses higher than the current accepted dose of 20–30 ml/kg/h in the critically ill patient with AKI. Peritoneal dialysis (PD) is avoided in patients with ALF due to a number of issues: potential for bleeding, risk of peritonitis and difficulty in fluid balance control. In addition, PD does not appear to clear solutes in hypercatabolic patients to an acceptable level compared with continuous RRT [17]. This may be due to the fact that many patients have deranged peritoneal blood flow which may be further hindered by norepinephrine and other vasoconstrictive agents often used in critically ill patients [55]. Patients with ALF are at increased risk of hemorrhage. Accordingly, many of these patients can be managed with anticoagulant-free continuous RRT circuits, especially if predilution fluid replacement is performed. Nonetheless, some patients clot their circuits. This may be due to the fact that while producing inadequate clotting factors, the damaged liver may also be producing insufficient quantities of numerous anticoagulants such as proteins S and C and antithrombin [54]. Decreased antithrombin III levels in ALF can limit the effect of heparin as an anticoagulant [54]. An alternative anticoagulation regime in ALF is to use a regional anticoagulant over the RRT circuit, such as the calcium chelator citrate, the serine protease inhibitors nafamostat maleate and kallikrein or prostanoids [54]. Citrate can enter the systemic circulation causing hypocalcemia, hypernatremia and aggravation of the metabolic acidosis common in patients with ALF. Similarly, lactate-containing replacement fluids or dialysate can result in lactate accumulation www.expert-reviews.com
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and promote acidosis, therefore bicarbonate dialysate may be preferred. Dialysis methodologies as therapy in ALF
Use of alternative dialysis methodologies such as high absorption hemofiltration or hybrid techniques including plasmapheresis and use of artificial kidneys have been reported in septic patients with AKI, but their role in management of such patients remains to be clarified [60]. Plasmapheresis may provide benefit in patients with ALF [61]. Artificial liver support systems exist (MARS or ‘molecular adsorbents recycling system’) which both remove water-soluble and albuminbound toxins from the blood in ALF and also provide some renal support in case of renal failure. The RELIEF trial randomized patients with acute on chronic liver failure into MARS or standard medical therapy groups and reported a 20% reduction in serum creatinine in the MARS group between trial entry and day 4 (during which the patients had daily treatment for 8 h with MARS). After day 4, the patients had 3 per week MARS treatments until day 21, however no change in serum creatinine was observed in this latter treatment period [62], suggesting intensive possibly daily MARS treatments are needed to achieve significant dialysis effect. In a randomized controlled trial of patients with hepato-renal syndrome, MARS significantly prolonged survival [63]. The FULMAR randomized trial is only available in abstract form; in this study patients with ALF had a trend to improved survival in the MARS group, but the study phase was very limited due to the high percentage of patients receiving emergency liver transplantation and in very short time frames (median 16.2 h between listing and operation) [64]. The Prometheus system is based on fractional plasma separation and adsorption and hemodialysis [65]. In a study involving 10 patients with hepato-renal syndrome, significant improvements in renal and liver function was seen but not survival [66]. Pharmacological interventions
General measures in the patient with ALF complicated with AKI include withdrawal of potentially nephrotoxic medication and avoidance of drugs associated with renal injury. AKI in these patients also requires careful consideration of medications metabolized or excreted mainly by the kidneys and appropriate dose adjustment when considered essential. In particular, treatment of raised ICP may utilize mannitol or thiopentone. The former therapy can result in volume overload, electrolyte imbalance and serum osmolarity changes and is further reasoning behind the early introduction of RRT in critically ill patients with ALF. Frequent complicating sepsis in patients with ALF and AKI requires considered antibiotic utilization and dosage. Previous studies of pharmacological interventions in patients with AKI, such as erythropoietin, have shown no beneficial effect. However, a randomized controlled trial has demonstrated treatment with the selective agonist of renal 707
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dopaminergic receptors, fenoldopam, prevents the development of AKI in patients with sepsis. Infusion of alkaline phosphatase started within 48 h of septic AKI onset improved creatinine clearance but requirement for RRT and duration was similar to placebo. Interestingly, systemic markers of inflammation were also reduced with alkaline phosphatase infusion in this trial [67]. However, it is not clear whether these pharmacological agents will be useful in patients with AKI associated with ALF. Outcomes/prognostication of AKI in patients with ALF
Development of AKI in patients with ALF is associated with adverse clinical outcomes. A large retrospective study demonstrated patients with ALF and AKI have longer hospital admissions and reduced spontaneous survival. No relationship between AKI and liver transplantation was observed, but transplanted patients who had AKI preoperatively had a longer postoperative hospital stay and a trend toward reduced survival to hospital discharge. However, AKI at the time of emergency liver transplantation was not associated with increased risk of chronic renal impairment during long-term follow-up [68]. Researchers investigating patients with ALF following liver resection reported a mortality rate of 66.3% those with AKI requiring RRT [56]. Other authors have reported AKI to be predictive of a poorer prognosis in both acetaminophen- and nonacetaminophen-induced ALF [1,8,69]. Impaired renal function at admission predicts a poorer outcome in acetaminophen overdose-induced ALF and serum creatinine concentration greater than 300 mmol/l are generally applied along with other criteria in the UK to indicate the need for emergency liver transplantation [70,71]. In a study examining patients with AKI and acetaminopheninduced hepatotoxicity, 51% of patients had returned to normal renal function at the time of discharge. However, 7% remained on dialysis and required transfer to their local renal unit but no patient required long-term dialysis. In this study, AKI was also associated with longer hospital stay [12]. Recent developments
In addition to definition of the condition, understanding of pathogenesis and dialysis as therapy as discussed above, the most recent advances in AKI management relate to the search for more reliable biomarkers for the purposes of early Box 1. Summary of key renal biomarkers investigated to date. Renal biomarkers • Cystatin-C: Marker of glomerular filtration • NGAL: Marker of renal injury, predictor of RRT • Human KIM-1: Predicts RRT and recovery • IL-18: Marker of proximal tubular injury • NAG: Marker of tubular injury NAG: N-acetyl-b-D-glucosaminidase; NGAL: Neutrophil gelatinase-ssociated lipocalin; RRT: Renal replacement therapy.
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recognition and accurate diagnosis, prognosis, monitoring of response to therapy and differentiating between AKI subtypes. These advances may help clinicians answer the ‘RRT initiation conundrum’ and better allocate donated livers for transplantation. The most accurate methods for measuring estimated GFR (i.e., by injecting radioisotopes and radio-contrast agents such as iohexol) are expensive and impractical in the critically ill patient. Oliguria can be difficult to quantify in a ward-based care setting and has several causes unrelated to AKI. The current biomarkers of urea and creatinine are relatively easy and cheap to measure, but they have issues of limited sensitivity, do not change until significant renal function has already been lost and cannot differentiate between renal dysfunction and ongoing injury processes. A further disadvantage is that as the injured liver fails to convert ammonia to urea, blood urea levels fall, masking deteriorating renal function. Additionally, the validity of urine-based measurements is difficult to assess if low urine output or anuria exists, hence part of the appeal of plasma biomarkers [24]. Novel biomarkers (BOX 1) could identify AKI earlier than changes in serum creatinine, characterize the mechanisms of renal damage in AKI, allow dynamic monitoring of renal injury and hence the effects of intervention and allow prediction of recovery. Biomarkers fall into one of two groups: proteins that are normally absent, but are upregulated during cellular injury or proteins that are normally present in renal tubular epithelial cells and released into the urine secondary to cell injury or necrosis [17]. Cystatin-C is a 120 amino acid lysosomal proteinase inhibitor manufactured by all nucleate cells. Unlike creatinine, cystatin-C is freely filtered across the glomerulus but not secreted by renal epithelial cells. Declining glomerular filtration results in rising blood cystatin-C levels, which occur earlier than increased creatinine concentrations [18]. The processing costs are considerably higher and cystatin-C is more a marker of glomerular filtration than acute tubular injury. Neutrophil gelatinase-associated lipocalin (NGAL), a protein expressed by epithelial cells in the proximal tubule and neutrophils that helps inhibit bacterial growth, is increased in the blood and urine within 2 h of renal injury and predicts the need for RRT in patients with AKI in the ITU [72]. However, in more heterogeneous populations, NGAL levels are less specific for detection of early AKI [17] and may be elevated in sepsis and in chronic renal impairment [24]. In a recent study of 241 patients with cirrhosis, NGAL levels were found to be helpful in determining the different causes of renal impairment, such as hepato-renal syndrome and pre-renal failure due to volume depletion [73]. Human kidney injury molecule-1 (KIM-1) is a glycoprotein with an immunoglobulin segment that is expressed and then shed at very high concentrations by proximal tubule epithelial cells after ischemic or toxic renal injury. High urinary levels are associated with mortality and the need for RRT in patients with AKI. Levels of KIM-1 may also predict recovery. However, there have not been any studies to date Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
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Acute kidney injury in acute liver failure
investigating the potential of this biomarker in the context of liver disease. IL-18, a pro-inflammatory cytokine and DAMP, has shown to predict mortality of patients with acute respiratory distress syndrome who developed AKI and may increase as a marker of proximal tubular injury in ATN. However, circulating blood levels are also increased in inflammatory, autoimmune diseases and sepsis [24]. Increased urinary IL-18 has been reported in patients with AKI 24 h after liver transplant [74] and elevated levels are also observed in ALF, which are correlated with serum creatinine. N-Acetyl-b-D-glucosaminidase (NAG) is a lysosomal enzyme found chiefly in proximal tubules. Increased NAG concentrations in the urine suggest tubular cell injury and remain persistently elevated in active kidney disease. Unfortunately, NAG excretion is also elevated in glomerular diseases such as diabetic nephropathy which limits its clinical potential. Several further molecules such as netrin-1, monocyte chemotactic peptide-1 + + [24] and the Na /H exchanger isoform 3 (NHE3) are under investigation as potential biomarkers of AKI [75]. To date, these emerging biomarkers have been reported in a limited number of publications in select groups of patients or in animal models. Further studies in a variety of populations are necessary in order to determine the applicability of these biomarkers to AKI in differing settings, especially in ALF [17]. As characterization of renal injury develops utilising these novel biomarkers, the concept of incipient renal injury has been proposed, in which biomarker changes identify an ‘atrisk kidney’ and inform need for preemptive therapy. Incipient AKI occurs before the development of creatinine rise. Potential therapy has been suggested to include appropriate fluid resuscitation, the potentially controversial recommendation for the prescription of angiotensin-converting inhibitors or receptor blockers and intelligent application of diuretic therapy [47]. Expert commentary
The study of renal disease in the context of ALF over the next 10 years is an area with the exciting prospect of new diagnostic and prognostic paradigms being established and a greater understanding of the best management strategies. Novel renal biomarkers are likely to be identified and validated and, if processing costs can be reduced, may serve in the future in determining which patients will require additional renal support and informing decisions regarding emergency liver transplantation. Similarly, various potential therapeutic targets (such as endothelin-1 antagonists, TLR4 antagonists or Bcl-xl agonists) show promise in animal models. If this can be replicated in patient studies these modalities could be exciting treatment prospects for the future and have significant positive effects on patient hospital stay and outcomes. Currently, what must not be overlooked are the basics of good clinical evaluation and management in patients with ALF, including close monitoring of clinical condition, www.expert-reviews.com
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traditional blood parameters and glucose levels, aggressive fluid hydration, adequate nutrition and avoiding nephrotoxic drugs and diuretics. Furthermore, physicians should always consider the kidneys at risk in patients with acetaminophen-induced ALF and monitor particularly closely renal function in such patients. Multidisciplinary involvement of hepatologists, intensivists and nephrologists in patients care will, as with many other areas of medicine, improve patient outcomes. Five-year view
Owing to the rarity of ALF, the study of AKI in this setting is challenging. Therefore, there remain many unanswered questions regarding both the pathogenesis and management of this common and serious complication in this clinical setting. Novel ammonia-lowering therapies might be pursued by targeting renal ammonia genesis, but there is little evidence of any successful therapies emerging via this route at present [44]. Further questions worthy of investigation include investigation of biomarkers that allow early detection of AKI, track response to therapy and aid prediction of prognosis. Also, further clarification of specific blood pressure and cardiac output targets to ensure appropriate renal perfusion in ALF and further studies evaluating the efficacy of albumin compared with crystalloid fluid replacement in maintaining adequate GFR in hypoalbuminemic patients would be helpful [18]. The relative success of RRT has prompted many researchers to focus on attempts at similar treatments for the liver. HepatAssist, a porcine bioartificial liver based on hepatocytes showed promise in a small randomized trial of patients with ALF and sub-ALF, nevertheless, the device has not been approved by the US FDA, and further trials were recommended [8]. The ideal therapy, of course, would be the use of an external device that could take over both liver and renal functions until suitable donor organs were obtained, if possible, similar to MARS or Prometheus. As with many clinical conditions, the potential for stem cell therapy in AKI has been explored, mainly in experimental animals. However, a few clinical studies have reported the safety and efficacy of mesenchymal stem cell infusion in patients with AKI. The potential for such therapy to positively influence the progression of ALF suggests a possible future without recourse to emergency liver transplantation for treatment of these potentially fatal combination of organ failures [76]. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. 709
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Key issues • Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). • AKI is associated with adverse clinical outcomes in this clinical situation. AKI is associated with longer hospital stays and increased mortality, but does not appear to result in increased risk of chronic renal failure during long-term follow-up. • Acetaminophen-induced ALF is the most common etiology of ALF associated with AKI and the kidneys should always be considered ‘at risk’ in such patients.
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• Studies show that adequate fluid replacement is essential and continuous renal replacement therapy is preferable to intermittent dialysis due to the risk of hypotensive episodes and risk of aggravating intracranial hypertension. • Biomarkers for renal injury remain an area of study and might aid early diagnosis and clinical decision-making regarding the use of renal replacement therapy and liver transplant allocation. • Further targets for future therapies include renal ammonia excretion, tubular cell death and renal inflammation. • Hope also remains that a successful external hepatic replacement therapy may be developed in the future for clinical practice allowing greater numbers of critically ill patients to survive until a liver transplant becomes available or potentially replace transplantation completely.
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Pickkers P, Heemskerk S, Schouten J et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomised double-blind placebo-controlled trial. Crit. Care 16(1), R14 (2012).
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Leithead JA, Ferguson JW, Bates CM, Davidson JS, Simpson KJ, Hayes PC. Chronic kidney disease after liver transplantation for acute liver failure is not associated with perioperative renal dysfunction. Am. J. Transplant. 11(9), 1905–1915 (2011).
Banares R, Nevens F, Larsen FS et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 57(3), 1153–1162 (2013). Stange J, Hassanein TI, Mehta R, Mitzner SR, Bartlett RH. The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers. Artif. Organs 26(2), 103–110 (2002). Saliba F, Camus C, Durand F et al. Randomised controlled multicentre trial evaluating the efficacy and safety of albumin dialysis with MARS in patients with fulminant and subfulminant hepatic failure. Presented at: The 59th Annual meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–4 November 2008.
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Cerda J, Tolwani A, Gibney N, Tiranathanagul K. Renal replacement therapy in special settings: extracorporeal support devices in liver failure. Semin. Dial. 24(2), 197–202 (2011).
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Barshes NR, Lee TC, Balkrishnan R, Karpen SJ, Carter BA, Goss JA. Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure. Transplantation 81(2), 195–201 (2006). Pakravan N, Simpson KJ, Waring WS, Bates CM, Bateman DN. Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit. Eur. J. Clin. Pharmacol. 65(2), 163–168 (2009). Lines SW, Wood A, Bellamy MC, Lewington AJ. The outcomes of critically ill patients with combined severe acute liver and kidney injury secondary to paracetamol
toxicity requiring renal replacement therapy. Renal. Failure 33(8), 785–788 (2011) •
Retrospective review over a 6-year period of the outcomes of patients with both acute liver and kidney injury secondary to paracetamol overdose admitted to the Intensive Care Unit of a University Teaching Hospital which has an active liver transplant program.
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Bennett M, Dent CL, Ma Q et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin. J. Am. Soc. Nephrol. 3(3), 665–673 (2008).
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Sirota JC, Walcher A, Faubel S et al. Urine IL-18, NGAL, IL-8 and serum IL-8 are biomarkers of acute kidney injury following liver transplantation. BMC Nephrol. 14, 17 (2013).
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Coca SG, Parikh CR. Urinary biomarkers for acute kidney injury: perspectives on translation. Clin. J. Am. Soc. Nephrol. 3(2), 481–490 (2008).
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A succinct review of the diagnostic and prognostic performace of various urinary biomarkers.
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Acute kidney injury in acute liver failure: a review Expert Rev. Gastroenterol. Hepatol. 7(8), 701–712 (2013)
Joanna K Moore1, Eleanor Love1, Darren G Craig2, Peter C Hayes3 and Kenneth J Simpson*3 1 Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Little France, Edinburgh, EH16 4SA, UK 2 Gastroenterology Department, James Cook University Hospital, South Tees NHS Foundation Trust, Middlesbrough, TS4 3BW, UK 3 Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, EH16 4SA, UK *Author for correspondence: Tel.: +44 131 242 1717 Fax: +44 131 242 1633 [email protected]
www.expert-reviews.com
Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review. KEYWORDS: acute kidney injury • acute liver failure • renal biomarkers
Acute (or fulminant) liver failure (ALF) is an uncommon clinical condition. Annual cases reported in the USA are estimated to be approximately 2000 cases per year [1], and in the UK approximately 1–8 cases per million population [2]. There are many causes of ALF, such as drug reactions, viral hepatitis, autoimmunity, acute fatty liver of pregnancy or hemolysis, elevated liver enzymes and low platelets, Wilson’s disease and shock. However, no identifiable cause is reported in up to 15% of cases, so-called non-A–E or seronegative hepatitis [3]. The relative frequency of these different etiologies varies in different parts of the world. In the developing world, the most common cause of ALF is viral infection; by contrast, acetaminophen (paracetamol) overdose is the leading cause in most Western populations [4]. ALF should not be confused with the separate entity of acute-on-chronic liver failure which occurs in cirrhotic patients and is discussed in a separate review in this journal [5]. The presenting clinical features of ALF are non-specific, including anorexia, fatigue, abdominal pain, jaundice and fever before progressing to hepatic encephalopathy (HE) [4]. HE is the cardinal clinical feature differentiating severe liver injury from ALF. As the condition progresses, intracranial pressure (ICP) may increase due to the development of cerebral edema. Coagulation abnormalities are 10.1586/17474124.2013.837264
common, but significant bleeding is relatively rare, explained by the balanced coagulation state recently reported in patients with ALF [6]. Electrolyte disturbances are also common, with hypoglycemia particularly dangerous. Hypotension, peripheral vasodilatation and respiratory failure may precede the development of multiorgan failure and death [4]. Clinical features of the systemic inflammatory response [7] are commonly reported in the absence of infection. However, sepsis is frequently observed and a common mode of death in patients with ALF [8]. General good supportive intensive care has improved the prognosis of patients with ALF. However, emergency liver transplantation is a life-saving procedure in highly selected individuals. Bioartificial liver support has shown some promise [9], usually applied to ‘bridge’ patients to emergency transplantation, but artificial liver support has yet to be translated into general clinical practice. Many patients with ALF develop acute kidney injury (AKI) [10]. The occurrence of AKI in the context of ALF is associated with increased morbidity and mortality. In the UK, deteriorating renal function or elevated serum creatinine (>300 mmol/l) are included in the transplant listing criteria for acetaminopheninduced ALF [11]. However, recovery of renal function is the norm following spontaneous
2013 Informa UK Ltd
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survival or emergency liver transplantation [12]. Improved understanding of the pathogenesis of AKI associated with ALF should inform the identification of better biomarkers of renal dysfunction, aid prognostication and potentially the development of novel therapies; these topics are discussed in more detail in this expert review.
criteria that is now generally accepted and widely applied [14]. Although the newer classification added small but important modifications to the definition of AKI, there are few reported differences in the diagnostic or prognostic performance (TABLE 1). A recent working party suggested the definition of AKI in patients with cirrhosis should be expanded to include all causes of acute deterioration in renal function defined as an increase in serum creatinine of >50% from baseline or a rise in serum creatinine >26.4 mmol/l (>0.3 mg/dl) in 0.3 mg/dl (>26.4 mmol/l) or >150–200% of the basal value
6 h
2
Increased serum creatinine >200–300% basal value
12 h
3
Increased serum creatinine >300% basal value, or serum creatinine >4.0 mg/dl (>354 mmol/l) with an acute increase of at least 0.5 mg/dl (44 mmol/l)
500 ml/day is a commonly used criterion for withdrawal of RRT. In a recent review of patients with acetaminophen-induced AKI, recovery of renal function prior to discharge from a tertiary referral center was associated with female gender, lower admission mean arterial blood pressure, day 3 MELD score and AKI stage [12]. Two landmark multicenter randomized controlled trials have been published, designed to examine the question of ‘dosage’ of RRT [58,59]. Researchers compared ‘less intensive’ with ‘intensive’ RRT and neither demonstrated any survival benefit with continuous RRT doses higher than the current accepted dose of 20–30 ml/kg/h in the critically ill patient with AKI. Peritoneal dialysis (PD) is avoided in patients with ALF due to a number of issues: potential for bleeding, risk of peritonitis and difficulty in fluid balance control. In addition, PD does not appear to clear solutes in hypercatabolic patients to an acceptable level compared with continuous RRT [17]. This may be due to the fact that many patients have deranged peritoneal blood flow which may be further hindered by norepinephrine and other vasoconstrictive agents often used in critically ill patients [55]. Patients with ALF are at increased risk of hemorrhage. Accordingly, many of these patients can be managed with anticoagulant-free continuous RRT circuits, especially if predilution fluid replacement is performed. Nonetheless, some patients clot their circuits. This may be due to the fact that while producing inadequate clotting factors, the damaged liver may also be producing insufficient quantities of numerous anticoagulants such as proteins S and C and antithrombin [54]. Decreased antithrombin III levels in ALF can limit the effect of heparin as an anticoagulant [54]. An alternative anticoagulation regime in ALF is to use a regional anticoagulant over the RRT circuit, such as the calcium chelator citrate, the serine protease inhibitors nafamostat maleate and kallikrein or prostanoids [54]. Citrate can enter the systemic circulation causing hypocalcemia, hypernatremia and aggravation of the metabolic acidosis common in patients with ALF. Similarly, lactate-containing replacement fluids or dialysate can result in lactate accumulation www.expert-reviews.com
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and promote acidosis, therefore bicarbonate dialysate may be preferred. Dialysis methodologies as therapy in ALF
Use of alternative dialysis methodologies such as high absorption hemofiltration or hybrid techniques including plasmapheresis and use of artificial kidneys have been reported in septic patients with AKI, but their role in management of such patients remains to be clarified [60]. Plasmapheresis may provide benefit in patients with ALF [61]. Artificial liver support systems exist (MARS or ‘molecular adsorbents recycling system’) which both remove water-soluble and albuminbound toxins from the blood in ALF and also provide some renal support in case of renal failure. The RELIEF trial randomized patients with acute on chronic liver failure into MARS or standard medical therapy groups and reported a 20% reduction in serum creatinine in the MARS group between trial entry and day 4 (during which the patients had daily treatment for 8 h with MARS). After day 4, the patients had 3 per week MARS treatments until day 21, however no change in serum creatinine was observed in this latter treatment period [62], suggesting intensive possibly daily MARS treatments are needed to achieve significant dialysis effect. In a randomized controlled trial of patients with hepato-renal syndrome, MARS significantly prolonged survival [63]. The FULMAR randomized trial is only available in abstract form; in this study patients with ALF had a trend to improved survival in the MARS group, but the study phase was very limited due to the high percentage of patients receiving emergency liver transplantation and in very short time frames (median 16.2 h between listing and operation) [64]. The Prometheus system is based on fractional plasma separation and adsorption and hemodialysis [65]. In a study involving 10 patients with hepato-renal syndrome, significant improvements in renal and liver function was seen but not survival [66]. Pharmacological interventions
General measures in the patient with ALF complicated with AKI include withdrawal of potentially nephrotoxic medication and avoidance of drugs associated with renal injury. AKI in these patients also requires careful consideration of medications metabolized or excreted mainly by the kidneys and appropriate dose adjustment when considered essential. In particular, treatment of raised ICP may utilize mannitol or thiopentone. The former therapy can result in volume overload, electrolyte imbalance and serum osmolarity changes and is further reasoning behind the early introduction of RRT in critically ill patients with ALF. Frequent complicating sepsis in patients with ALF and AKI requires considered antibiotic utilization and dosage. Previous studies of pharmacological interventions in patients with AKI, such as erythropoietin, have shown no beneficial effect. However, a randomized controlled trial has demonstrated treatment with the selective agonist of renal 707
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dopaminergic receptors, fenoldopam, prevents the development of AKI in patients with sepsis. Infusion of alkaline phosphatase started within 48 h of septic AKI onset improved creatinine clearance but requirement for RRT and duration was similar to placebo. Interestingly, systemic markers of inflammation were also reduced with alkaline phosphatase infusion in this trial [67]. However, it is not clear whether these pharmacological agents will be useful in patients with AKI associated with ALF. Outcomes/prognostication of AKI in patients with ALF
Development of AKI in patients with ALF is associated with adverse clinical outcomes. A large retrospective study demonstrated patients with ALF and AKI have longer hospital admissions and reduced spontaneous survival. No relationship between AKI and liver transplantation was observed, but transplanted patients who had AKI preoperatively had a longer postoperative hospital stay and a trend toward reduced survival to hospital discharge. However, AKI at the time of emergency liver transplantation was not associated with increased risk of chronic renal impairment during long-term follow-up [68]. Researchers investigating patients with ALF following liver resection reported a mortality rate of 66.3% those with AKI requiring RRT [56]. Other authors have reported AKI to be predictive of a poorer prognosis in both acetaminophen- and nonacetaminophen-induced ALF [1,8,69]. Impaired renal function at admission predicts a poorer outcome in acetaminophen overdose-induced ALF and serum creatinine concentration greater than 300 mmol/l are generally applied along with other criteria in the UK to indicate the need for emergency liver transplantation [70,71]. In a study examining patients with AKI and acetaminopheninduced hepatotoxicity, 51% of patients had returned to normal renal function at the time of discharge. However, 7% remained on dialysis and required transfer to their local renal unit but no patient required long-term dialysis. In this study, AKI was also associated with longer hospital stay [12]. Recent developments
In addition to definition of the condition, understanding of pathogenesis and dialysis as therapy as discussed above, the most recent advances in AKI management relate to the search for more reliable biomarkers for the purposes of early Box 1. Summary of key renal biomarkers investigated to date. Renal biomarkers • Cystatin-C: Marker of glomerular filtration • NGAL: Marker of renal injury, predictor of RRT • Human KIM-1: Predicts RRT and recovery • IL-18: Marker of proximal tubular injury • NAG: Marker of tubular injury NAG: N-acetyl-b-D-glucosaminidase; NGAL: Neutrophil gelatinase-ssociated lipocalin; RRT: Renal replacement therapy.
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recognition and accurate diagnosis, prognosis, monitoring of response to therapy and differentiating between AKI subtypes. These advances may help clinicians answer the ‘RRT initiation conundrum’ and better allocate donated livers for transplantation. The most accurate methods for measuring estimated GFR (i.e., by injecting radioisotopes and radio-contrast agents such as iohexol) are expensive and impractical in the critically ill patient. Oliguria can be difficult to quantify in a ward-based care setting and has several causes unrelated to AKI. The current biomarkers of urea and creatinine are relatively easy and cheap to measure, but they have issues of limited sensitivity, do not change until significant renal function has already been lost and cannot differentiate between renal dysfunction and ongoing injury processes. A further disadvantage is that as the injured liver fails to convert ammonia to urea, blood urea levels fall, masking deteriorating renal function. Additionally, the validity of urine-based measurements is difficult to assess if low urine output or anuria exists, hence part of the appeal of plasma biomarkers [24]. Novel biomarkers (BOX 1) could identify AKI earlier than changes in serum creatinine, characterize the mechanisms of renal damage in AKI, allow dynamic monitoring of renal injury and hence the effects of intervention and allow prediction of recovery. Biomarkers fall into one of two groups: proteins that are normally absent, but are upregulated during cellular injury or proteins that are normally present in renal tubular epithelial cells and released into the urine secondary to cell injury or necrosis [17]. Cystatin-C is a 120 amino acid lysosomal proteinase inhibitor manufactured by all nucleate cells. Unlike creatinine, cystatin-C is freely filtered across the glomerulus but not secreted by renal epithelial cells. Declining glomerular filtration results in rising blood cystatin-C levels, which occur earlier than increased creatinine concentrations [18]. The processing costs are considerably higher and cystatin-C is more a marker of glomerular filtration than acute tubular injury. Neutrophil gelatinase-associated lipocalin (NGAL), a protein expressed by epithelial cells in the proximal tubule and neutrophils that helps inhibit bacterial growth, is increased in the blood and urine within 2 h of renal injury and predicts the need for RRT in patients with AKI in the ITU [72]. However, in more heterogeneous populations, NGAL levels are less specific for detection of early AKI [17] and may be elevated in sepsis and in chronic renal impairment [24]. In a recent study of 241 patients with cirrhosis, NGAL levels were found to be helpful in determining the different causes of renal impairment, such as hepato-renal syndrome and pre-renal failure due to volume depletion [73]. Human kidney injury molecule-1 (KIM-1) is a glycoprotein with an immunoglobulin segment that is expressed and then shed at very high concentrations by proximal tubule epithelial cells after ischemic or toxic renal injury. High urinary levels are associated with mortality and the need for RRT in patients with AKI. Levels of KIM-1 may also predict recovery. However, there have not been any studies to date Expert Rev. Gastroenterol. Hepatol. 7(8), (2013)
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Acute kidney injury in acute liver failure
investigating the potential of this biomarker in the context of liver disease. IL-18, a pro-inflammatory cytokine and DAMP, has shown to predict mortality of patients with acute respiratory distress syndrome who developed AKI and may increase as a marker of proximal tubular injury in ATN. However, circulating blood levels are also increased in inflammatory, autoimmune diseases and sepsis [24]. Increased urinary IL-18 has been reported in patients with AKI 24 h after liver transplant [74] and elevated levels are also observed in ALF, which are correlated with serum creatinine. N-Acetyl-b-D-glucosaminidase (NAG) is a lysosomal enzyme found chiefly in proximal tubules. Increased NAG concentrations in the urine suggest tubular cell injury and remain persistently elevated in active kidney disease. Unfortunately, NAG excretion is also elevated in glomerular diseases such as diabetic nephropathy which limits its clinical potential. Several further molecules such as netrin-1, monocyte chemotactic peptide-1 + + [24] and the Na /H exchanger isoform 3 (NHE3) are under investigation as potential biomarkers of AKI [75]. To date, these emerging biomarkers have been reported in a limited number of publications in select groups of patients or in animal models. Further studies in a variety of populations are necessary in order to determine the applicability of these biomarkers to AKI in differing settings, especially in ALF [17]. As characterization of renal injury develops utilising these novel biomarkers, the concept of incipient renal injury has been proposed, in which biomarker changes identify an ‘atrisk kidney’ and inform need for preemptive therapy. Incipient AKI occurs before the development of creatinine rise. Potential therapy has been suggested to include appropriate fluid resuscitation, the potentially controversial recommendation for the prescription of angiotensin-converting inhibitors or receptor blockers and intelligent application of diuretic therapy [47]. Expert commentary
The study of renal disease in the context of ALF over the next 10 years is an area with the exciting prospect of new diagnostic and prognostic paradigms being established and a greater understanding of the best management strategies. Novel renal biomarkers are likely to be identified and validated and, if processing costs can be reduced, may serve in the future in determining which patients will require additional renal support and informing decisions regarding emergency liver transplantation. Similarly, various potential therapeutic targets (such as endothelin-1 antagonists, TLR4 antagonists or Bcl-xl agonists) show promise in animal models. If this can be replicated in patient studies these modalities could be exciting treatment prospects for the future and have significant positive effects on patient hospital stay and outcomes. Currently, what must not be overlooked are the basics of good clinical evaluation and management in patients with ALF, including close monitoring of clinical condition, www.expert-reviews.com
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traditional blood parameters and glucose levels, aggressive fluid hydration, adequate nutrition and avoiding nephrotoxic drugs and diuretics. Furthermore, physicians should always consider the kidneys at risk in patients with acetaminophen-induced ALF and monitor particularly closely renal function in such patients. Multidisciplinary involvement of hepatologists, intensivists and nephrologists in patients care will, as with many other areas of medicine, improve patient outcomes. Five-year view
Owing to the rarity of ALF, the study of AKI in this setting is challenging. Therefore, there remain many unanswered questions regarding both the pathogenesis and management of this common and serious complication in this clinical setting. Novel ammonia-lowering therapies might be pursued by targeting renal ammonia genesis, but there is little evidence of any successful therapies emerging via this route at present [44]. Further questions worthy of investigation include investigation of biomarkers that allow early detection of AKI, track response to therapy and aid prediction of prognosis. Also, further clarification of specific blood pressure and cardiac output targets to ensure appropriate renal perfusion in ALF and further studies evaluating the efficacy of albumin compared with crystalloid fluid replacement in maintaining adequate GFR in hypoalbuminemic patients would be helpful [18]. The relative success of RRT has prompted many researchers to focus on attempts at similar treatments for the liver. HepatAssist, a porcine bioartificial liver based on hepatocytes showed promise in a small randomized trial of patients with ALF and sub-ALF, nevertheless, the device has not been approved by the US FDA, and further trials were recommended [8]. The ideal therapy, of course, would be the use of an external device that could take over both liver and renal functions until suitable donor organs were obtained, if possible, similar to MARS or Prometheus. As with many clinical conditions, the potential for stem cell therapy in AKI has been explored, mainly in experimental animals. However, a few clinical studies have reported the safety and efficacy of mesenchymal stem cell infusion in patients with AKI. The potential for such therapy to positively influence the progression of ALF suggests a possible future without recourse to emergency liver transplantation for treatment of these potentially fatal combination of organ failures [76]. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. 709
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Key issues • Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). • AKI is associated with adverse clinical outcomes in this clinical situation. AKI is associated with longer hospital stays and increased mortality, but does not appear to result in increased risk of chronic renal failure during long-term follow-up. • Acetaminophen-induced ALF is the most common etiology of ALF associated with AKI and the kidneys should always be considered ‘at risk’ in such patients.
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• Studies show that adequate fluid replacement is essential and continuous renal replacement therapy is preferable to intermittent dialysis due to the risk of hypotensive episodes and risk of aggravating intracranial hypertension. • Biomarkers for renal injury remain an area of study and might aid early diagnosis and clinical decision-making regarding the use of renal replacement therapy and liver transplant allocation. • Further targets for future therapies include renal ammonia excretion, tubular cell death and renal inflammation. • Hope also remains that a successful external hepatic replacement therapy may be developed in the future for clinical practice allowing greater numbers of critically ill patients to survive until a liver transplant becomes available or potentially replace transplantation completely.
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