Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation

Tacrolimus(Tac)is currently the most common calcineurin-inhibitor employed in solid organ transplantation.High intra-patient variability(IPV)of Tac(Tac IPV)has been associated with an increased risk of immune-mediated rejection and poor outcomes after kidney transplantation.Few data are available concerning the impact of high Tac IPV in non-kidney transplants.However,even in kidney transplantation,there is still a controversy whether high Tac IPV is indeed detrimental in respect to graft and/or patient survival.This may be due to different methods employed to evaluate IPV and distinct time frames adopted to assess graft and patient survival in those reports published up to now in the literature.Little is also known about the influence of high Tac IPV in the development of other untoward adverse events,update of the current knowledge regarding the impact of Tac IPV in different outcomes following kidney,liver,heart,lung,and pancreas tran-splantation to better evaluate its use in clinical practice.

Primary prophylaxis of variceal bleeding in patients with cirrhosis:A comparison of different strategies

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%,and,when variceal hemorrhage develops,mortality reaches 20%.Patients are deemed at high risk of bleeding when they present with medium or large-sized varices,when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size.In order to avoid variceal bleeding and death,individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis,for which currently recommended strategies are the use of traditional non-selective beta-blockers(NSBBs)(i.e.,propranolol or nadolol),carvedilol(a NSBB with additional alpha-adrenergic blocking effect)or endoscopic variceal ligation(EVL).The superiority of one of these alternatives over the others is controversial.While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode,either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction,probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension.A sequential strategy,in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment,or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.

Cumulative positive fluid balance is a risk factor for acute kidney injury and requirement for renal replacement therapy after liver transplantation

AIM To analyze whether fluid overload is an independent risk factor of adverse outcomes after liver transplantation(LT).METHODS One hundred and twenty-one patients submitted to LT were retrospectively evaluated.Data regarding perioperative and postoperative variables previously associated with adverse outcomes after LT were reviewed.Cumulative fluid balance(FB) in the first 12 h and 4 d after surgery were compared with major adverse outcomes after LT.RESULTS Most of the patients were submitted to a liberal approach of fluid administration with a mean cumulative FBover 5 L and 10 L,respectively,in the first 12 h and 4 d after LT.Cumulative FB in 4 d was independently associated with occurrence of both AKI and requirement for renal replacement therapy(RRT)(OR = 2.3;95%CI:1.37-3.86,P = 0.02 and OR = 2.89;95%CI:1.52-5.49,P = 0.001 respectively).Other variables on multivariate analysis associated with AKI and RRT were,respectively,male sex and Acute Physiology and Chronic Health Disease Classification System(APACHE II) levels and sepsis or septic shock.Mortality was shown to be independently related to AST and APACHE II levels(OR = 2.35;95%CI:1.1-5.05,P = 0.02 and 2.63;95%CI:1.0-6.87,P = 0.04 respectively),probably reflecting the degree of graft dysfunction and severity of early postoperative course of LT.No effect of FB on mortality after LT was disclosed.CONCLUSION Cumulative positive FB over 4 d after LT is independently associated with the development of AKI and the requirement of RRT.Survival was not independently related to FB,but to surrogate markers of graft dysfunction and severity of postoperative course of LT.

Albumin administration in patients with cirrhosis: Current role and novel perspectives

Mortality in cirrhosis is mostly associated with the development of clinical decompensation,characterized by ascites,hepatic encephalopathy,variceal bleeding,or jaundice.Therefore,it is important to prevent and manage such complications.Traditionally,the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis,but it is currently understood that decompensation might also be driven by a systemic inflammatory state(the systemic inflammation hypothesis).Considering its oncotic and nononcotic properties,albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events.There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis,patients with spontaneous bacterial peritonitis,those with acute kidney injury(even before the etiological diagnosis),and those with hepatorenal syndrome.Moreover,there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites(long-term albumin administration),individuals with hepatic encephalopathy,and those with acute-on-chronic liver failure undergoing modest-volume paracentesis.Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications,such as individuals with extraperitoneal infections,those hospitalized with decompensated cirrhosis and hypoalbuminemia,and patients with hyponatremia.

Renal failure in cirrhosis: Emerging concepts

Acute renal failure, now termed acute kidney injury(AKI), is frequently found in patients with cirrhosis. The occurrence of AKI, irrespective of the underlying cause, is associated with reduced in-hospital, 3-mo and 1-year survival. Hepatorenal syndrome is associated with the worst outcome among AKI patients with cirrhosis. Several definitions for AKI that have been proposed are outlined and evaluated in this paper. Among these, the International Club for Ascites-AKI criteria substantially strengthen the quality of early diagnosis and intervention according to underlying cause of AKI.