Renal failure in patients with cirrhosis: a changing paradigma

Transcription

1 Renal failure in patients with cirrhosis: a changing paradigma P. Angeli, Dept. of Medicine, Unit of Hepatic Emergencies and Liver Transplantation, University of Padova (Italy) pangeli@unipd.it 47th Annual Meeting of the Italian Association for the Study of the Liver Disease Rome February 20th-21st, 2014

2 Agenda Definitions Diagnostic approach Treatment Future perspectives

3 Definition of renal failure in cirrhosis The traditional diagnostic criteria of renal failure in cirrhosis were proposed 17 years ago and have been improved in subsequent years. It is based on the presence of a serum creatinine 1.5 mg/dl which represents a GFR below 40 ml/min. V. Arroyo et al. Hepatology 1996 ; 23 : Salerno F. et al. Gut 2007 ; 56 :

4 MANAGEMENT OF PATIENTS WITH CIRRHOSIS Pittfalls related to the use of serum creatinine (scr) as a marker of glomerular filtration rate (GFR) Creatine is synthesized in the liver before being stored in muscles where it is phosphorylated as creatinine. This small compound is freely filtered by the kidney but it can also be secreted by the proximal tubule. The ratio between creatinine secreted by the tubule to the amount of creatinine filtered by the glomerulus increases as GFR decreases. In the general population creatinine is influenced by age, gender and ethnicity. Several reasons make that in cirrhotic patients, scr can further overestimate GFR: Impaired liver function results in decreased creatinine production. Protein-calorie malnutrition and muscle wasting which are common during cirrhosis also contribute to decreased creatinine production. An high ratio between creatinine secreted by the proximal tubule and creatine filtered by the glomerulus can develop. C. Francoz et al. J. Hepatol ; 52 :

5 6 MANAGEMENT OF PATIENTS WITH CIRRHOSIS Relationship between serum creatinine and glomerular filtration rate measured by inulin clearance (mgfr) Serum creatinine (mg/dl) mgfr (ml/min/1.73 m 2 ) L. Caregaro et al. Arch. Intern. Med ; 154 :

6 Definition of renal failure in cirrhosis Should we change current definition and diagnostic criteria of renal failure in cirrhosis? V. Arroyo J. Hepatol ; 59 :

7 Why to review our current definition? Because there are new data that challenge the threshold value of 1.5 mg/dl serum creatinine in the definition of renal failure.

8 Relationship between GFR (ml/min 1.73 m 2 ) measured by inulin clearance (mgfr) serum creatinine (scr) scr (mg/dl) 1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0, mgfr S. Rosi et al ; AASLD (abstract)

9 Why to review our current definition? Because there are new data that challenge the threshold value of 1.5 mg/dl serum creatinine in the definition of renal failure. Because we did not have a clear cut timeframe to differentiate acute and chronic renal failure. Because new definitions for chronic renal disease (CKD) and acute kidney injury (AKI) have been proposed.

10 National Kidney Foundation Kidney Disease Outcome Quality Initiative: Classification of CKD Chronic kidney disease is defined as either kidney damage or decreased kidney function (decreased GFR) for 3 or more months With kidney damage Without kidney damage GFR (ml/min/1.73m 2 ) Stage Stage >/= 90 1 Normal Decreased GFR* < * may be normal for age Levey AS et al. Ann. Intern. Med ; 139 :

11 Is the definition of CKD suitable to patients with cirrhosis? Chronic kidney disease has connotations that may not be fair to patients with cirrhosis, in particular: - It has been based on the application of formulas for the estimation of glomerular filtration rate.

12 Absolute bias of the formulas in the estimation of the imapirment of measured Glomerular filtration rate (mgfr) Formula mgfr > 90 (ml/min/1,73 m 2 ) (n =93) 60 mgfr 90 (ml/min/1,73 m 2 ) (n =78) 30 mgfr < 60 (ml/min/1,73 m 2 ) (n =32) mgfr < 30 (ml/min/1,73 m 2 ) (n =10) CKD-EPI (ml/min/1,73 m 2 ) (-29.1 : -18.1) 6.0 (1.2 ; 10.8) 27.1 (19.9 ; 34.3) 47.5 (38.8; 56.2) MDRD4 (ml/min/1,73 m 2 ) (- 24 : - 5.7) 14.6 (3.4 ; 15.7) 29.5 (20.7 ; 38.4) 46.0 (38.1 ; 53.9) MDRD7 (ml/min/1,73 m 2 ) (-29.3 ; -16.4) 3.7 (-2.0 ; ; 9.5) 23.8 (16.0 ; 31.6) 43.3 (33.5 ; 53.0) S. Rosi et al ; AASLD (abstract)

13 Is the definition of CKD suitable to patients with cirrhosis? Chronic kidney disease has connotations that may not be fair to patients with cirrhosis, in particular: - It has been based on the application of formulas for the estimation of glomerular filtration rate - It implies the concept of irreversibility

14 Percent of responders to terlipressin and albumin according to type of HRS % % % 20 0 Type 1 HRS Type 2 HRS M. Martin-Llhai et al. Gastroenterology 2008 ; 134 :

15 Definition of CKD in patients with cirrhosis Since, terminology is very very important a better term for the the chronic impiarment of renal function in patients with cirrhosis might be Chronic Kidney Dysfunction. A new marker for GFR is needed for the definition of CKD. Serum creatinine-base formulas may dectect a measured GFR < 60 ml/min/1.73 m 2 in less that 50 % of patients with cirrhosis.

16 Prevalence of AKI and CKD in patients with cirrhosis and serum sreatinine > 1.5 mg/dl admitted to the hospital 100 % 70 % % 13 % AKI AKI+CKD CKD N.S. Warner et al. J. Investig. Med ; 59 :

17 Ninety day mortality as a function of the presence of AKI or CKD in hospitalized patients with cirrhosis M. Martin Llahi et al. Gastroenterology ; 140 :

18 Definition and of Acute Renal Failure Conventional criteria = a rapid reduction in kidney function currently defined as a percentage increase in serum creatinine of more or equal to 50 % (1.5-fold from baseline) to a final value equal or higher than 1.5 mg/dl. P. Ginès at al. N Engl J Med 1991;325: P. Sort et al. N Engl J Med 1999;341: A. Ginès et al. Gastroenterology. 1996;111: P. Angeli et al. Gut 2010;59:

19 Definition and staging of Acute Kidney Injury (AKI) KDIGO criteria = an abrupt (within 48 hours) reduction in kidney function currently defined as an absolute increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4 µmol/l), or a percentage increase in serum creatinine of more or equal to 50 % (1.5-fold from baseline) in less than 7 days. Stage Serum creatinine criteria Increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4 µmol/l) or a percentage increase in serum creatinine of more or equal to 50 % (1.5-fold from baseline). Increase in serum creatinine to more than 200% to 300% (> 2- to 3-fold) from baseline Increase in serum creatinine to more than 300 % (> 3-fold) from baseline or serum creatinine of more or equal to 4.0 mg/dl ( 354 µmol/l) with an acute increase of at least 0.5 mg/dl (44 µmol/l) or need for renal replacement therapy KDIGO AKI Work Group Kidney Int. Suppl ; 2 : R.L. Mehta et al. Crit. Care 2007 ; 11 : R31.

20 Outcome according to renal status in patients with cirrhosis and bacterial infection Parameter Pts with AKI (n = 166) Pts without AKI (n = 171) P N of deaths 68 (34 %) 12 (7 %) < Pts transferred to ICU 76 (46%) 35 (20%) < Lenght of hospital stay (days) 17.8 ± ± 31.8 < F. Wong et al. Gastroeterology (Epub ahead of print)

21 Accuracy of conventional criterion vs KDIGO criteria in the prediction of in-hospital mortality in a series of 233 patients with cirrhosis and ascites Criteria Sensibility 95 % CI Specificity 95% CI PPV 95% CI NPV 95% CI LR+ 95% CI LR- 95% CI Conventional criterion ( ) ( ) ( ) ( ) ( ) ( ) KDIGO criteria ( ) ( ) ( ) ( ) ( ) ( ) S. Piano et al. J. Hepatol ; 59 :

22 Initial AKI stage and in-hospital mortality P< P< P< P<0.025 P=N.S. 20 P< No AKIN AKI stage 1 AKI stage 2 AKI stage 3 Serum creatinine < 1.5 mg/dl S. Piano et al. J. Hepatol ; 59 :

23 Dynamics of AKI stage after initially fullfilling KDIGO criteria (1) Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%) 11.4 % 15.9 % 44.4 % 72.7 % 65.6 % Peak Stage 1 (52.5%) Peak Stage 2 (16.4%) Peak Stage 3 (31.2%) S. Piano et al. J. Hepatol ; 59 :

24 Accuracy of conventional criterion vs KDIGO criteria in the prediction of in-hospital mortality in a series of 233 patients with cirrhosis and ascites Criteria Sensibility 95 % CI Specificity 95% CI PPV 95% CI NPV 95% CI LR+ 95% CI LR- 95% CI Conventional criterion ( ) ( ) ( ) ( ) ( ) ( ) KDIGO criteria ( ) ( ) ( ) ( ) ( ) ( ) KDIGO with Progression ( ) ( ) ( ) ( ) ( ) ( ) S. Piano et al. J. Hepatol ; 59 :

25 Characteristics of patients with and without progression of initial stage of Acute Kidney Injury (AKI) Non-progressors (n = 37) Progressors (n = 16) Age (years) mean (SD) 67.4 (10.6) 70.4 (7) Gender M/F n (%) 20 (54%) / 17 (46%) 8 (50%) / 8 (50%) 1.00 Child Pugh score median (min-max) 10 (5-14) 10.5 (5-14) MELD score median (min-max) 19 (9-38) 21 (11-37) Albumin (g/dl) median (min-max) 2.7 ( ) 2.7 ( ) Bilirubin (µmol/l) median (min-max) 63.3 ( ) 85.3( ) Protrombin time (%) mean (SD) 45.3 (13.9) 48.4 (16.0) Baseline scr (mg/dl) median (min-max) 1.1 ( ) 1.2 ( ) Baseline scr 1.5 mg/dl n (%) 14 (37.8) 5 (31.3) scr 1.5 mg/dl at diagnosis of AKI n (%) 19 (51.4) 15 (93.7) Bacterial infections n (%) 24 (64.9) 11 (68.8) Leukocyte counts el/µl median (min-max) 6,500 (1,240-18,480) 6,170 (2,750-13,570) P S. Piano et al. J. Hepatol ; 59 :

26 Survival of in hospitalized patients with cirrhosis according to Acute Kidney Injury (AKI). # = with peak creatinine level <1.5 mg/dl, * = with peak creatinine level 1.5 mg/dl C. Fagundes et al. J. Hepatol ; 59 :

27 Dynamics of AKI stage after initially fullfilling KDIGO criteria (2) Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%) 11.4 % 15.9 % 44.4 % 72.7 % 65.6 % Peak Stage 1 (52.5%) Peak Stage 2 (16.4%) Peak Stage 3 (31.2%) 62.5 % 40 % 36.8 % Resolution S. Piano et al. J. Hepatol ; 59 :

28 Probability of AKIN 1 stage regression according to the cut off of 1.5 of serum creatinine (scr) % p < scr < 1.5 mg/dl scr > 1.5 mg/dl - S. Piano et al. J. Hepatol ; 59 :

29 Patient survival with the acute kidney injury (AKI) and non-aki groups CD. Tsien et al. Gut 2013 ; 62 :

30 Agenda Definitions Diagnostic approach Treatment Future perspectives

31 Proposal of an algorithm for AKI management Initial AKI# stage 1 and scr < 1.5 mg/dl Initial AKI# stage 1 and scr 1.5 mg/dl or initial AKI# stage > 1 Close monitoring Remove risk factors (withdrawal of nephrotoxic drugs, vasodilators and NSADs, taper/withdraw diuretics treat infections*when diagnosed) Withdrawal of diuretics (if not yet applied) and volume expansion with albumin (1g/kg) for 2 days Progression? Response? NO YES YES NO Close follow up Does AKI Meet criteria of HRS? #= AKI at the first fulfilling of AKIN crieria NO YES = scr at the first fulfilling of AKIN crieria * Treatment of SBP includes albumin infusion Specific treatment for other AKI phenotypes Terlipressin and albumin S. Piano et al. J. Hepatol ; 59 :

32 Clinical consequences of the proposed algorithm for AKI management in patients with cirrhosis (1) The acceptance of the main point that derived from the application of KDIGO criteria that is to focus attention on and to manage promptly even small increases in serum creatinine The maintainance of a serum creatinine cut off value (1.5 mg/dl) not to define AKI but to titrate its treatment A more rationale application of the therapeutic resources (avoiding of potentially dangerous consequences of an overtreatment of AKI as a consequence of an uncritical application of the AKIN criteria) S. Piano et al. J. Hepatol ; 59 :

33 Phenotypes of AKI in patients with cirrhosis and ascites 1. Acute tubular necrosis (41.7%) 2. Prerenal failure (38%) 3. Hepatorenal syndrome (20%) 4. Postrenal failure (0.3%) R. Moreau et al. Hepatology 2003 ; 37 :

34 Ninety day mortality as a function of the phenotypes of AKI in hospitalized patients with cirrhosis p <0.005 M. Martin Llahi et al. Gastroenterology ; 140 :

35 Definition of HRS HRS is a functional renal failure caused by intrarenal vasoconstriction which occurs in patients with end stage liver disease as well as in patients with acute liver failure or alcoholic hepatitis. HRS is characterized by impaired renal function, marked alterations in cardiovascular function, and overactivity in the endogenous vasoactive systems. F. Salerno et al. Gut 2007 ; 56 :

36 Current diagnostic criteria 1. Cirrhosis with ascites; 2. Serum creatinine > 133 µmol/l (1.5 mg/dl); 3. No sustained improvement of serum creatinine (decrease to a level of 133 µmol/l or less) after at least two days of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day to a maximum of 100 g/day; 4. Absence of shock 5. No current or recent treatment with nephrotoxic drugs; 6. Absence of parenchimal disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography. F. Salerno, et al. Gut 2007 ; 56 :

37 Serum creatinine > 1.5 mg/dl for 3 months CKD/type 2 HRS* AKI/type 1 HRS* * Proteinuria < 0.5 g/l and no hematuria JM. Trawale et al. Liver Int ; 30 :

38 Serum creatinine levels >1.5 mg/dl Proteinuria > 0.5 g/day Haematuria JM. Trawale et al. Liver Int ; 30 :

39 Renal vascular injury 10 (18) 12 (18) 13 (18) Acute tubulointerstitial injury Chronic tubulointerstitial injury JM. Trawale et al. Liver Int ; 30 :

40 Urinary neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with acute tubular necrosis (ATN) and different types of hepatorenal syndrome µg/g creatinine N.S. P < < N.S. P < ATN HRS associated with infection HRS Type 1 HRS Type 2 C. Fagundes et al. J. Hepatol ; 57 :

41 Agenda Definitions Diagnostic approach Treatment Future perspectives

42 Pharmacologic therapy for HRS Albumin (20-40 g/day intravenously) Terlipressin (0.5-2 mg/4-6hr intravenously) J. Uriz et al. J. Hepatol ; 33 :

43 Patients with response to treatment % P < P < Group A (Terlipressin) All responders Group B (Midodrine + Octreotide) Full responders M. Cavallin et. al. (manuscript submitted)

44 Responders to the treatment at day 15th (%) P = N.S % 40 % 0 Noradrenalin Terlipressin P. Sharma et al. Am. J. Gastroenterol ; 103:

45 Peripheral arterial vasodilation hypothesis Portal hypertension/liver failure Increased release of NO, CO and other vasodilators Terlipressin Splanchnic arterial vasodilation Albumin Reduction of effective circulating volume Maximal activation of endogenous vasocontrictor systems Severe renal arterial vasoconstriction RW. Schrier, et al. Hepatology 1988 ; 8 : (revised)

46 Effect of terlipressin on renal arterial resistive index Renal arterial resistive index P < Y. Narahara et al. J. Gastroenterol. Hepatol ; 24 :

47 Terlipressin and albumin vs albumin in cirrhotic patients with ascites and type 1 HRS in two controlled clinical trials Spain Trial (n = 45) 1 USA Trial (n = 112) 2 Terlipressin and albumin Albumin Terlipressin and albumin Placebo and/or albumin Response (%) 43.5%* 8.7% 34%# 13% Survival (%) At 3 months 27 % At 3 months 19 % At 6 months 13 % At 6 months 9% * = p <0.025 ; # = p < ) M. Martin-Llhai et al. Gastroenterology 2008 ; 134 : ) A. Sanyal et al. Gastroenterology 2008 ; 134 :

48 A meta-analysis of terlipressin alone or with albumin versus no interentation or albumin in patients with HRS Mortality Solanki 2003 Sanyal 2008 Neri 2008 Martin Llahi 2008 Yang 2001 TOTAL Favours treatment Favours control LL. Gluud et al. Cochrane 2012

49 The facts Vasoconstrictors and albumin are effective in less of 50 % of patients with type 1 HRS. Vasoconstrictor and albumin improve survival slightly. Vasoconsctrictors and albumin can not be used in all patients with type 1 HRS. In up to 25 % of patients the treatment should be discontinued for adverse effects. High cost of treatment. P. Angeli et al. Liver Int ; 33 :

50 Limitations of terlipressin plus albumin Inherent Extrinsic

51 Definition of HRS HRS is a functional renal failure caused by intrarenal vasoconstriction which occurs in patients with end stage liver disease as well as in patients with acute liver failure or alcoholic hepatitis. HRS is characterized by impaired renal function, marked alterations in cardiovascular function, and overactivity in the endogenous vasoactive systems. F. Salerno et al. Gut 2007 ; 56 :

52 500 NGAL urinary levels in patients with type 1 HRS according to the response to terlipressin and albumin (ng/ml) p < Full responders Partial or non responders M. Cavallin et. al. AASLD 2011.

53 Peripheral arterial vasodilation hypothesis Portal hypertension/liver failure Increased release of NO, CO and other vasodilators Terlipressin Splanchnic arterial vasodilation Albumin Reduction of effective circulating volume Maximal activation of endogenous vasocontrictor systems Severe renal arterial vasoconstriction RW. Schrier, et al. Hepatology 1988 ; 8 : (revised)

54 Systemic heamodynamics before and after the onset of HRS after the resolution of SBP HRS after SBP resolution No HRS after SBP resolution P MAP (mm Hg) 73±8 83±8 < SVR (dyn sec/cm ) 1268± ±226 N.S. Plasma NE (pg/ml) ± ±195.3 <.025 CO (l/min) 4.6± ±2.0 < 0.01 RAP (mm Hg) 4.6± ±1.7 N.S. PCWP (mm Hg) 7.4 ± ±2.3 N.S. HR (bpm) 87±9 79±16 N.S. L. Ruiz-del-Arbol et. al. Hepatology 2003 ; 38 :

55 Peripheral arterial vasodilation hypothesis (revised) Portal hypertension/liver failure Increased release of NO, CO and other vasodilators? Splanchnic arterial vasodilation Splanchnic arterial vasodilation Reduced cardiac output Reduction of effective circulating volume Maximal activation of endogenous vasocontrictor systems Severe renal arterial vasoconstriction RW. Schrier et al. Hepatology 1988 ; 8 : (revised)

56 Systemic hemodynamics at baseline and 30 min. after terlipressin in patients with cirrhosis and ascites Parameter Baseline After terlipressin P Heart rate (bpm) 83 ± ± 16 < Mean arterial pressure (mm Hg) 89 ± ± 14 < Systemic vascular resistance (dynes/s cm 5 ) 1295 ± ± 465 < Cardiac output (l/min) 5.2 ± ± 1.1 < 0.05 Pulmonary capillary wedged pressure (mm Hg) 9.6 ± ± 2.6 < Y. Narahara et al. J. Gastroenterol. Hepatol ; 24 :

57 Limitations of terlipressin plus albumin Inherent Extrinsic

58 Clinical types of HRS Type 1 HRS : rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level > 226 µmol/l or 2.5 mg/dl in less than two weeks. It may occurs spontaneously, but it can also follow a precipitating event. Clinical pattern: acute renal failure Type 2: is characterized by moderate renal failure (serum creatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with a steady or slowly progressive course. Clinical pattern: refractory ascites F. Salerno, et al. Gut 2007 ; 56 :

59 % Response to tretament (%) according to the baseline serum creatinine value Renal failure in cirrhosis mg/dl < 3-5 mg/dl > 5.0 mg/dl T.D. Boyer et al. J. Hepatol ; 55 ;

60 Relationship between MAP and serum creatinine (SCr) in HRS Baseline SCr Required SCr to achieve goal (%) Predicted increase in MAP to achieve SCr goal (mm Hg) (25%) 3.7 ( ) (30%) 8.5 ( ) (62.5%) 13.3 ( ) J.C. Q. Velez et al. Am. J. Kidney Dis ; 58 :

61 Proposal of an algorithm for AKI management Initial AKI# stage 1 and scr < 1.5 mg/dl From 0.6 to 0.9 mg/dl Close monitoring Remove risk factors (withdrawal of nephrotoxic drugs, vasodilators and NSADs, taper/withdraw diuretics treat infections*when diagnosed) Initial AKI# stage 1 and scr 1.5 mg/dl or initial AKI# stage > 1 Withdrawal of diuretics (if not yet applied) and volume expansion with albumin (1g/kg) for 2 days Progression? Response? NO YES From 0.9 to 1.2 mg/dl YES NO From 1.2 to 1.4 mg/dl Close follow up Does AKI Meet criteria of HRS? #= AKI at the first fulfilling of AKIN crieria NO YES = scr at the first fulfilling of AKIN crieria * Treatment of SBP includes albumin infusion Specific treatment for other AKI phenotypes Terlipressin and albumin S. Piano et al. J. Hepatol ; 59 :

62 Clinical consequences of our proposal of an algorithm for AKI management (2) The acceptance of the main point that derived from the application of AKIN criteria that is to focus attention on and to manage promptly even small increases in serum creatinine The maintainance of a serum creatinine cut off value (1.5 mg/dl) not to define AKI but to titrate its treatment. A more rationale application of the therapeutic resources (avoiding of potentially dangerous consequences of an overtreatment of AKI as a consequence of an uncritical application of the AKIN criteria) A clear dinstinction between AKI and hepatorenal syndrome (which is only one of the possible phenotypes of AKI) The definitive removal of the cut off of serum creatinine 1.5 mg/dl from the criteria for diagnosis of HRS in the setting of AKI. S. Piano et al. J. Hepatol ; 59 :

63 The facts Vasoconstrictors and albumin are effective in less of 50 % of patients with type 1 HRS. Vasoconstrictors and albumin improve survival slightly. Vasoconsctrictors and albumin can not be used in all patients with type 1 HRS. In up to 25 % of patients the treatment should be discontinued for adverse effects. High cost of treatment. P. Angeli et al. Liver Int ; 33 :

64 Survival in patients according to the treatment of type 1 HRS % LT Responders to terlipressin and albumin Responders to terlipressin plus albumin Non responders to terlipressin and albumin Non responders to terlipressin plus albumin days T.D. Boyer et al. Liver Transpl ; 17 :

65 Probability of survival in patients treated for Type 1 hepatorenal syndrome according to improvement of renal function % 1 0,8 0,6 Responders 0,4 0,2 P < Non responders days M. Martin-Llhai et al. Gastroenterology 2008 ; 134 :

66 How to optimize the results of pharmacological treatment for type 1 HRS in the perspective of LT? In responders In non responders

67 Mortality according to the pharmacological treatment of HRS and LT Variable Hazards ratio for mortality 95% confidence interval P Mortality independent from LT < Overall mortality < J.P. Rice et al. Transplantation 2011 ; 91 :

68 Relationship between MELD score and estimated 3-month probability of survival according to type of HRS C. Alessandria et al. Hepatology 2005 ; 41 :

69 Mean reduction of the MELD score in responders Terlipressin Midodrine + octreotide M. Cavallin et. al. (manuscript submitted).

70 Effect of change in 1 MELD point in LT waiting time in US days UNOS Regions Overall TD. Boyer (personal comunication)

71 Time from HRS to LT days P < Responders Non responders J.P. Rice et al. Transplantation 2011 ; 91 :

72 Probability of survival in patients treated for Type 1 hepatorenal syndrome according to improvement of renal function % 1 0,8 0,6 Responders 0,4 0,2 P < Non responders days M. Martin-Llhai et al. Gastroenterology 2008 ; 134 :

73 Proposal for a new policy to assure an high priority to LT to patients with type 1 HRS who responded to the treatment with vasoconstrictors and albumin Patients with type 1 HRS have probably the highest priority to LT, but run the risk of remaining on the waiting list for months simply because their MELD and MELD-Na are reduced by the treatment. For this reason, we have put forward a proposal to resolve this paradoxical situation by highlighting two different clinical scenarios: - Patient A: patient who responds to terlipressin and albumin and then maintains an adequate renal function In this patient we proposed using for the definition of the priority in the waiting list to LT the baseline MELD or MELD-Na. P. Angeli et al. J. Hepatol 2012 ; 57 :

74 Probability of survival in patients treated for Type 1 hepatorenal syndrome according to improvement of renal function % 1 0,8 0,6 0,4 Responders Baseline MELD = 30 0,2 P < Non responders days M. Martin-Llhai et al. Gastroenterology 2008 ; 134 :

75 Proposal for a new policy to assure an high priority to liver transplantation to the patients with type 1 HRS who responded to the treatment with vasoconstrictors and albumin Patients with type 1 HRS have probably the highest priority to LT, but run the risk of remaining on the waiting list for months simply because their MELD and MELD-Na are reduced by the treatment. For this reason, we have put forward a proposal to resolve this paradoxical situation by highlighting two different clinical scenarios: - Patient B: patient who experiences continuous recurrence of type 1 HRS whenever the discontinuation of tretament is attempted. P. Angeli et al. J. Hepatol 2012 ; 57 :

76 Time course of serum creatinine and treatment with terlipressin and albumin in patient with continuous recurrence of type 1 HRS MELD = 30 MELD Na = 35 MELD = 19 MELD Na = 19 S. Piano et al. J. Hepatol 2011 ; 55 :

77 Liver transplant policy in Italy: exceptions to the MELD scores Statement on hepatorenal syndrome Type 1 HRS and severe type 2 HRS (serum creatinine > 2 mg/dl) should be considered an exception to the MELD Na score (I, A). For the patient with type 1 HRS and severe type 2 HRS who responds to terlipressin and albumin and then maintains an adequate renal function, pre-treatment* MELD-Na score should be used for prioritization in the waiting list to LT (III, B). For the patient with continuous recurrence of type 1 or severe type 2 HRS who requires a long term treatment of type 1 HRS, the treatment with terlipressin and albumin should be included in the calculation of MELD Na score, as it is already provided for renal replacement therapy (III, B). P. Angeli et al. J. Hepatol 2012 ; 57 : Italian Society of Organ Transplantation

78 How to optimize the pharmacological treatment for type 1 HRS? In responders In non responders

79 Helios Study: 28-day transplant free survival in subgroup of patients with type 1 HRS Day 90 Diff. ~ 36%; p<0.05 Day 28 Diff. ~ 23%; NS A. Kribben et al. Gastroenterology ; 142 :

80 Outcome of patients with type 1 HRS after liver transplantation (LT) 28 pts with type 1 HRS 8 pts prelt-rrt 6 pts prelt-rrt 16 pts recover renal function 12 pts did not recover renal function P.E. Marik et al. Nephrol. Dial. Transpl ; 21 : pts develop CDK

81 500 Renal failure in cirrhosis NGAL urinary levels in patients with type 1 HRS according to the response to terlipressin and albumin (ng/ml) p < Full responders Partial or non responders M. Cavallin et. al. AASLD 2011.

82 The ratio of urinary excretion of γ-glutamyltranspeptidase to glomerular filtration rate in patients with type 1 HRS treated with vasonsctrictors and albumin * ** * = P < 0.05 ; ** = P < * 0 Normal range B D5 D10 B D5 D10 D20 Nonresponders Responders P. Angeli et al. Hepatology 1999 ; 29 :

83 Incidence of CKD stage 4 and 5 at 5 years after liver transplantation (LT) according to the phenotype of AKI at LT % P < HRS ATN M. Nadim et al. Liver Transpl ; 18 :

84 One and five year patient survival after liver transplantation (LT) according to the phenotype of AKI at LT P < 0.05 M. Nadim et al. Liver Transpl ; 18 :

85 a. CKD requiring dialysis b. CKD not requiring dialysis: Documentation of both GFR <=30 ml/min (by MDRD6 or iothalamate measurement) and proteinuria (> 3gms protein per day with 24 hr protein measurement or urine protein/creatinine ratio > 3) is required. c. d. e. Sustained AKI: Patients may also qualify for CLKT listing with a combination of time in categories (c) and (d) above for a total of six weeks. f. Metabolic Disease Renal failure in cirrhosis Current UNOS recommendations for combined kidney liver transplantation (CKLT) Sustained AKI requiring dialysis: Documentation of dialysis for 6 weeks or more (defined as dialysis at least twice a week for 6 consecutive weeks) is required. Sustained AKI not requiring dialysis: Documentation of a GFR <=25 ml/min for 6 weeks or more by MDRD6 or direct measurement (iothalamate or iohexol) is required at least once a week. Legend: CKD = chronic kidney disease ; GFR = glome rular filtration rate ; MDRD6 = modification of diet in renal disease formula 6 ; AKI = acute kidney ingiury JD. Eason et al. Am. J. Transplant ; 8 :

86 Agenda Definitions Diagnostic approach Treatment Future perspectives

87 Future perspectives To discover new biomarkers of glomerular filtration rate To discover new biomarkers of tubular damage To validate the new algorithm for the management of AKI To develop new treatments for patients with HRS who did not respond to vasonstrictors and albumin

88 Acknowledgements - Prof. A. Gatta - Dott. S. Piano - Prof. J. Rodes - Dott.ssa M. Cavallin - Prof. V. Arroyo - Dott. S. Fasolato - Dott.ssa A. Romano - Dott.ssa S. Rosi - Dott. F. Morando - Dott.ssa M.L. Stanco - Dott.ssa E. Gola - Dott.ssa A. Bortoluzzi - Sign.ra A. Sticca

89 Dedication