Acute Kidney Injury in Cirrhosis: A Changing Spectrum
Authors: Kevin Moore
Journal: Hepatology (2012)

AKI, acute kidney injury; HRS, hepatorenal syndrome. One of the big challenges that clinicians still face is the treatment of patients with cirrhosis who develop acute kidney injury or the hepatorenal syndrome (HRS). We have known for a long time that HRS represented a spectrum of pathology and pathophysiology, and this culminated in the publication in 1996 of the new criteria for the definition of HRS by the International Ascites Club of type 1 HRS and type 2 HRS.1 Without going into the definitions, in essence type 1 HRS is the rapid onset of renal failure that occurs in patients with rapid decompensation of cirrhosis due to either alcoholic hepatitis, or acute on chronic liver failure, or acute liver failure. Type 2 HRS is the type of renal impairment observed in patients with refractory ascites, with renal function fluctuating over a relatively long period of time. This definition was born out of necessity, mainly to facilitate research in the area since, prior to this date, patients tended to be clumped together when it was clear that clinically and presumably their underlying pathophysiology were different. While these definitions have helped us move on in terms of identifying mechanisms, the definitions have by virtue of their criteria probably held us back, by identifying patients late, and with relatively advanced renal failure. Thus, the definitions involve absolute serum creatinine values which we now know are inappropriate. Thus, a serum creatinine in a heavily built black muscular man are treated the same as an emaciated white female with advanced alcoholic liver disease. This definition bit us back when two clinical trials of terlipressin in HRS showed a response rate to treatment of 34%-40%,2, 3 probably because patients were randomized too late for true efficacy. We are now seeing articles that state predictability of response to terlipressin is determined by serum creatinine.4 Another way of putting this is that patients with early HRS respond better to treatment than patients with advanced kidney failure. In many ways this is "kind of obvious," so we need new criteria that can be adapted to individual patients. This was also recognized in the working party report of Wong et al.5 The development of HRS is due to four main factors. These are: (1) altered systemic hemodynamics with vasodilatation and lowering of arterial pressure; (2) activation of the sympathetic nervous system, which alters renal autoregulation such that renal blood flow becomes more dependent on arterial pressure; (3) a terminal decline in cardiac function due to cirrhotic cardiomyopathy, which renders patients unable to maintain an adequate cardiac output as they decompensate; and (4) increased circulating or intrarenal vasoactive mediators, the role of which remain unknown. Importantly, the role of each of these factors probably varies from patient to patient. The advent of the new definition of acute kidney injury (AKI) by the AKI network has led to a reevaluation and proposed new definitions for HRS.5 What is well recognized by all is that current criteria for HRS recognize and treat patients too late. This is important to rectify as soon as possible since presently the U.S. Food and Drug Administration (FDA) insist that therapeutic studies in HRS use current definitions, when this puts new therapeutic trials at risk of premature failure. The current article by Parikh et al. sets the scene for the future.6 They studied 192 patients with cirrhosis who developed acute kidney injury. In all, 44% of patients progressed in their stage of AKI, and nearly 50% of patients developed stage 3 AKI. Importantly, the authors observed that 60% of patients had evidence of AKI on admission to hospital, with the remaining 40% developing AKI during their hospitalization. Interestingly, mortality was significantly higher in those patients who developed AKI subsequent to admission than in those who presented with AKI, 36% versus 21%, respectively (P = 0.01). This clearly presents an opportunity to intervene in these patients earlier and thus decrease mortality. The severity of AKI worsened following the initial fulfillment of AKIN criteria in 85 (44%) of patients. In all, 12% had proteinuria which is roughly consistent with recent reports of chronic kidney disease in some patients with cirrhosis.6 It has become increasingly apparent over the years that bacterial infection plays a major role in all decompensating episodes such as variceal bleeding, hepatic encephalopathy. If we look at the underlying reasons associated with AKI in the patients with cirrhosis we see in the article by Belcher et al. that ∼20% have bacteremia, 20% have pneumonia, 30% have a urinary tract infection, and 25% have a gastrointestinal bleed.7 Thus, most patients have bacterial infection as a precipitating cause. While the role of endotoxemia and presumably infection as a cause of hepatorenal syndrome has been with us since the 1970s with work done by Steve Wilkinson and others,8, 9 it has taken us a long time to acknowledge this role. This study shows clearly how as one progresses from stage 1 (2% mortality) to stage 2 (15% mortality) to stage 3 (44% mortality), that the development or AKI is important for prognosis for patients with cirrhosis who develop AKI.6 In an article in press, Tsien and colleagues studied 90 patients with ascites over about 14 months with the objective of determining the prevalence of AKI in cirrhosis with ascites and the impact of AKI on patient outcomes. They observed that 82 episodes of AKI occurred in 49 patients, with the majority of episodes precipitated by a disturbance in systemic hemodynamics. AKI occurred in >50% patients with cirrhosis and ascites. In fact, for all the AKI episodes, there was a significant negative correlation between the peak serum creatinine and the simultaneous mean arterial pressure, and the development of AKI was accompanied by a transient fall in the mean arterial pressure from 89 ± 3 mm Hg to 76 ± 3 mmHg, which returned to baseline upon resolution of the AKI episodes.9 So what have we learned and where do we go from here? It is clear that AKI or HRS have major implications for survival. The current study by Belcher et al. highlights the fact that current criteria as defined by the International Ascites Club need revision. Current proposals for a working definition of HRS have largely adopted current AKI criteria,5 but we need to recognize the clinical reality that not all patients who might be classified as having type 1 HRS should necessarily be included in one grouping, and this is where current AKI criteria or the new proposals let us down. This is not just about putting patients into brackets or classifying them, it is about understanding the mechanisms of disease. Further, the current RIFLE criteria and indeed the proposals put forward by Wong et al.5 put patients with refractory ascites into a group with chronic kidney disease, and yet much of the renal dysfunction is entirely reversible. Belcher et al. recognized this dilemma when they state "We have avoided using the term 'chronic kidney disease' as this classically implies structural damage. Many patients with cirrhosis have a chronically depressed GFR due instead to persistent hypoperfusion and their renal function may thus be partially reconstituted with restitution of perfusion." The article by Belcher et al.7 highlights the need for all new definitions of HRS to recognize that patients with cirrhosis may develop acute kidney injury for a variety of reasons, many of which involve bacterial infection, or rapid decompensation of liver function (e.g., alcoholic hepatitis without infection), shock, administration of a nephrotoxic drug, as well as those having "true" chronic kidney disease, rather than renal hypoperfusion. We need to be able to identify patients early, both as new patients and importantly those patients who develop AKI following admission to the hospital, since this latter group have a higher mortality, and this should be preventable.6 What is the purpose of a definition of HRS? Why not just group everyone together as recently proposed?5 The purpose is to recognize the different clinical entities that arise so that we do not group all patients as being one and equal, but classify them so that we can increase our understanding of the underlying pathophysiology and develop targeted therapies. While it is clear from the two largest trials of terlipressin in HRS2, 3 that not all patients respond to therapy, we need to identify the different clinical entities that may respond to different therapies, in the same way that pharmacogenomics is beginning to identify subsets of patients who respond to certain drugs. The article by Parikh et al. highlights the problems and dilemmas we face.6 There are major problems with the current definition of HRS, but there are also problems if we simply adopt AKI criteria. We need robust criteria to classify patients so that our future therapies are individualized to the patient, so that they can be more effective.