Acute renal failure in patients with cirrhosis“Gastrolearning”Padova 8 Aprile 2013P. AngeliUnit of Hepatic Emergencies and...
• Diagnosis of AKI/HRS• Pharmacological treatment of HRSHepatorenal syndrome (HRS)Topics
Hepatorenal syndrome (HRS)Diagnosis of AKI/HRS
Phenotypes of renal dysfunction in patients with cirrhosisAKI in cirrhosisG. Garcia-Tsao et al. Hepatology 2008 ; 48 : 206...
Definition and staging of Acute Kidney Injury (AKI) according to AKINcriteriaR.L. Mehta et al. Crit. Care 2007 ; 11 : R31....
DefinitionAKI in cirrhosisFurther and larger prospective studies are needed to assessthe ability of new criteria versus th...
Criteria Sensibility95 % CISpecificity95% CIPPV95% CINPV95% CILR+95% CILR-95% CIConventional criterion 0.5152(0.33 - 0.69)...
Patient survival with the acute kidney injury (AKI) andnon-AKI groupsAKI in cirrhosisCD. Tsien et al. Gut 2013 ; 62 : 131-...
020406080100No AKIN AKI stage 1 AKI stage 2 AKI stage 3P<0.001P<0.0001P<0.0001P=N.S.P<0.025P<0.01Initial acute Kidney Inju...
Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%)Dynamics of AKI stage after initially fullfilling A...
Criteria Sensibility95 % CISpecificity95% CIPPV95% CINPV95% CILR+95% CILR-95% CIConventional criterion 0.5152(0.33 - 0.69)...
Non-progressors(n° = 37)Progressors(n° = 16)PAge (years) – mean (SD) 67.4 (10.6) 70.4 (7) 0.3707Gender M/F – n° (%) 20 (54...
%020406080100sCr < 1.5 mg/dl sCr > 1.5 mg/dl-Probability of AKIN stage progression according to the cut offof 1.5 of serum...
Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%)Dynamics of AKI stage after initially fullfilling A...
%020406080100sCr < 1.5 mg/dl sCr > 1.5 mg/dl-Probability of AKIN 1 stage regression accordind to the cut offof 1.5 of seru...
Proposal of an algorithm for AKI managementWithdrawal of diuretics (if notyet applied) and volumeexpansion with albumin(1g...
• The acceptance of the main point that derived from theapplication of AKIN criteria that is to focus attention on andto m...
Proposal of an algorithm for AKI managementWithdrawal of diuretics (if notyet applied) and volumeexpansion with albumin(1g...
Hepatorenal syndrome (HRS)Treatment of HRS
Pharmacologic therapy for HRS• Albumin (20-40 g/day intravenously)• Terlipressin (0.5-2 mg/4-6hr intravenously)J. Uriz et ...
Hepatorenal syndrome (HRS)020406080100Noradrenalin TerlipressinP. Sharma et al. Am. J. Gastroenterol. 2008 ; 103:1689–1697...
Hepatorenal syndrome (HRS)Cumulative probability of survival during therapy of patients treatedwith noradrenaline and terl...
Hepatorenal syndrome (HRS)050010001500200025003000Noradrenalin TerlipressinP. Sharma et al. Am. J. Gastroenterol. 2008 ; 1...
Patients with response to treatmentHepatorenal syndrome (HRS)020406080100Group A (Terlipressin) Group B (Midodrine + Octre...
Pharmacologic therapy for HRS• Albumin (20-40 g/day intravenously)• Terlipressin (0.5-2 mg/4-6hr intravenously)J. Uriz et ...
The facts• Vasoconstrictors and albumin are effective inless of 50 % of patients with type 1 HRS.• Vasoconstrictor and alb...
Limitations of terlipressin plus albumin• Inherent• ExtrinsicHepatorenal syndrome (HRS)
HRS is a functional renal failure caused by intrarenalvasoconstriction which occurs in patients with end stage liverdiseas...
CKD AKISerum creatinine > 1.5 mg/dl for ≥ 3 months/type 2 HRS* /type 1 HRS** Proteinuria < 0.5 g/l and no hematuriaHepator...
Serum creatinine levels >1.5 mg/dlProteinuria > 0.5 g/day Haematuria182095427JM. Trawale et al. Liver Int. 2010 ; 30 : 725...
Renal vascular injuryAcutetubulointerstitialinjuryChronictubulointerstitialinjury10 (18)13 (18)12 (18)JM. Trawale et al. L...
0100200300400no HRS HRSNGAL urinary levels in patients with cirrhosis andascites according to the diagnosis of type 1 HRSM...
0100200300400500Full responders Partial or non respondersp < 0.0025M. Cavallin. et. al. AASLD 2011NGAL urinary levels in p...
The ratio of urinary excretion of γ-glutamyltranspeptidaseto glomerular filtration rate in patients with type 1 HRStreated...
Peripheral arterial vasodilation “hypothesis”Portal hypertension/liver failureReduction of effective circulating volumeSev...
Hepatorenal syndrome (HRS)HRS after SBPresolutionNo HRS after SBPresolutionPMAP (mm Hg) 73±8 83±8 < 0.025SVR (dyn sec/cm )...
BaselineAt the diagnosis ofHRSPMAP (mm Hg) 80±975±7< 0.001HVPG (mm Hg) 19.5±3.020.0±4.0< 0.005SVR (dyn sec/cm ) 1158±285 1...
Peripheral arterial vasodilation “hypothesis” (revised)Portal hypertension/liver failureReduction of effective circulating...
Hepatorenal syndrome (HRS)Y. Narahara et al. J. Gastroenterol. Hepatol. 2009 ; 24 : 1791-1797Parameter BaselineAfterterlip...
Hepatorenal syndrome (HRS)ParameterContrlsubjects(n° = 46)Patients withcirrhosis andwithoutascites (n° =36)Patients withci...
Cardiac output in cirrhotic patients according to the Child-Pugh-Turcotte class3000600090001200015000Class A Class B Class...
05101520P < 0.005Overall transvascular transport of albumin incirrhosisJ. H. Henriksen et al. J. Hepatol. 2001 ; 34 : 53-6...
Effects of albumin on cardiac contractility in cirrhotic rats-10.0 -9.5 -9.0 -8.5 -8.00510152025∆LVDP(mmHg)ControlCirrhoti...
?Hepatorenal syndrome (HRS)
NAD(P)H•p67p47gp91rac•O2-O2 H+NAD(P)+p22phoxNADH/NADPH OxidaseThe NADPH/NADH oxidaseHepatorenal syndrome (HRS)
00,511,52control rats treated with V control rats treated with Arats with cirrhosis treated with V rats with cirrhosis tre...
?TNF-αHepatorenal syndrome (HRS)
00,20,40,60,811,21,41,61,8Control rats treatedwith VControl rats treatedwith ARats with cirrhosistreated with VRats with c...
Proteinexpression(foldofincrease)*#* p<0.05 vs controlsEffects of albumin on TNF-α protein expression in the cardiactissue...
Proteinexpression(foldofincrease)*#* p<0.05 vs controlsEffects of albumin on iNos protein expression in the cardiactissue ...
TNF-αHepatorenal syndrome (HRS)
?Hepatorenal syndrome (HRS)
* = p < 0.01 vs controllEffects of albumin on β-adgrenergic signaling in cardiac tissue according totreatement with saline...
Hepatorenal syndrome (HRS)
Limitations of terlipressin plus albumin• Inherent• ExtrinsicHepatorenal syndrome (HRS)
Response to tretament (%) according to the baseline serumcreatinine value01020304050603.0 mg/dl < 3 - 5 mg/dl > 5.0 mg/dlT...
Summary• The application of conventional criterion is more accurate than a formalapplication of AKIN criteria in the predi...
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L’insufficienza renale nel cirrotico - Gastrolearning®

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Gastrolearning XII lezione
L'insufficienza renale nel cirrotico - Prof. P. angeli (Università di Padova)

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L’insufficienza renale nel cirrotico - Gastrolearning®

  1. 1. Acute renal failure in patients with cirrhosis“Gastrolearning”Padova 8 Aprile 2013P. AngeliUnit of Hepatic Emergencies and Liver TransplantationDept. of MedicineUniversity of Padova, Italypangeli@unipd.it
  2. 2. • Diagnosis of AKI/HRS• Pharmacological treatment of HRSHepatorenal syndrome (HRS)Topics
  3. 3. Hepatorenal syndrome (HRS)Diagnosis of AKI/HRS
  4. 4. Phenotypes of renal dysfunction in patients with cirrhosisAKI in cirrhosisG. Garcia-Tsao et al. Hepatology 2008 ; 48 : 2064—2077 (modified).Definition of ARF/AKI = a rapid reduction in kidney functioncurrently defined as a percentage increase in serum creatinine of moreor equal to 50 % (1.5-fold from baseline) to a final value equal orhigher than 1.5 mg/dl.Hospitalized patients with cirrhosisARF/AKI(19%)CKD(1%)
  5. 5. Definition and staging of Acute Kidney Injury (AKI) according to AKINcriteriaR.L. Mehta et al. Crit. Care 2007 ; 11 : R31.Definition of AKI = an abrupt (within 48 hours) reduction in kidney functioncurrently defined as an absolute increase in serum creatinine of more than orequal to 0.3 mg/dl (≥ 26.4 μmol/l), or a percentage increase in serumcreatinine of more or equal to 50 % (1.5-fold from baseline).Stage Serum creatinine criteria1°Increase in serum creatinine equal or less than 200 % (≤ 2-fold ) frombaseline2°Increase in serum creatinine to more than 200% to 300% (> 2- to 3-fold)from baseline3°Increase in serum creatinine to more than 300 % (> 3-fold) from baselineor serum creatinine of more or equal to 4.0 mg/dl (≥ 354 μmol/l) with anacute increase of at least 0.5 mg/dl (44 μmol/l) or need for renalreplacement therapyAKI in cirrhosis
  6. 6. DefinitionAKI in cirrhosisFurther and larger prospective studies are needed to assessthe ability of new criteria versus the conventional criteria ofrenal dysfunction in the prediction of survival in patientswith cirrhosis.P. Angeli et al. Liver Int. 2012 (Epub ahead of print)
  7. 7. Criteria Sensibility95 % CISpecificity95% CIPPV95% CINPV95% CILR+95% CILR-95% CIConventional criterion 0.5152(0.33 - 0.69)0.9450(0.90 - 0.97)0.6071(0.40 - 0.78)0.9220(0.87 - 0.95)9.3664(4.8 - 18.17)0.5131(0.36 - 0.73)AKIN criteria 0.6667(0.48 - 0.82)0.8100(0.74 - 0.86)0.3667(0.24 - 0.50)0.9364(0.88 - 0.96)3.5088(2.41 - 5.10)0.4115( 0.25 - 0.66)Accuracy of conventional criterion vs AKIN criteria in the precition ofin-hospital mortality in a series of 233 patients with cirrhosis and ascitesS. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  8. 8. Patient survival with the acute kidney injury (AKI) andnon-AKI groupsAKI in cirrhosisCD. Tsien et al. Gut 2013 ; 62 : 131-137
  9. 9. 020406080100No AKIN AKI stage 1 AKI stage 2 AKI stage 3P<0.001P<0.0001P<0.0001P=N.S.P<0.025P<0.01Initial acute Kidney Injury Network (AKIN) stage (panel A) and in-hospital mortalityS. Piano et al. (J. Hepatol. 2013 ; in press)Serum creatinine < 1.5 mg/dlRenal failure in cirrhosis
  10. 10. Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%)Dynamics of AKI stage after initially fullfilling AKIN criteria (1)Peak Stage 1 (52.5%)72.7 %65.6 %Peak Stage 2 (16.4%)11.4 %Peak Stage 3 (31.2%)15.9 % 44.4 %S. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  11. 11. Criteria Sensibility95 % CISpecificity95% CIPPV95% CINPV95% CILR+95% CILR-95% CIConventional criterion 0.5152(0.33 - 0.69)0.9450(0.90 - 0.97)0.6071(0.40 - 0.78)0.9220(0.87 - 0.95)9.3664(4.8 - 18.17)0.5131(0.36 - 0.73)AKIN criteria 0.6667(0.48 - 0.82)0.8100(0.74 - 0.86)0.3667(0.24 - 0.50)0.9364(0.88 - 0.96)3.5088(2.41 - 5.10)0.4115( 0.25 - 0.66)AKIN withProgression0.5455(0.36 - 0.71)0.9450(0.90 - 0.97)0.6207(0.42 - 0.79)0.9265(0.88 - 0.95)9.9174(5.15 - 19.06)0.4810(0.33 - 0.70)Accuracy of conventional criterion vs AKIN criteria in the precition ofin-hospital mortality in a series of 233 patients with cirrhosis and ascitesS. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  12. 12. Non-progressors(n° = 37)Progressors(n° = 16)PAge (years) – mean (SD) 67.4 (10.6) 70.4 (7) 0.3707Gender M/F – n° (%) 20 (54%) / 17 (46%) 8 (50%) / 8 (50%) 1.00Child Pugh score – median (min-max) 10 (5-14) 10.5 (5-14) 0.9286MELD score – median (min-max) 19 (9-38) 21 (11-37) 0.5540Albumin (g/dl) – median (min-max) 2.7 (1.9-4.3) 2.7 (1.8-4.5) 0.8824Bilirubin (µmol/L) – median (min-max) 63.3 (7.9-477.8) 85.3(8.9-631) 0.5571Protrombin time (%) – mean (SD) 45.3 (13.9) 48.4 (16.0) 0.3563Baseline sCr (mg/dl) – median (min-max) 1.1 (0.48-3.0) 1.2 (0.7-2.9) 0.3090Baseline sCr ≥ 1.5 mg/dl – n (%) 14 (37.8) 5 (31.3) 0.736319 (51.4) 15 (93.7)Bacterial infections – n (%) 24 (64.9) 11 (68.8) 1.000Leukocyte counts el/µl – median (min-max) 6,500 (1,240-18,480)6,170 (2,750-13,570)0.9764Characteristics of patients with and without progression of initial stage of AcuteKidney Injury (AKI) according to the Acute Kidney Injury Network criteria(AKIN)S. Piano et al. (J. Hepatol. 2013 ; in press)0.0041sCr ≥ 1.5 mg/dl at diagnosis of AKI –n (%)Renal failure in cirrhosis
  13. 13. %020406080100sCr < 1.5 mg/dl sCr > 1.5 mg/dl-Probability of AKIN stage progression according to the cut offof 1.5 of serum creatinine (sCr)S. Piano et al. (J. Hepatol. 2013 ; in press)p < 0.01Renal failure in cirrhosis
  14. 14. Initial Stage 1 (72.1%) Initial Stage 2 (14.8%) Initial Stage 3 (13.1%)Dynamics of AKI stage after initially fullfilling AKIN criteria (2)Peak Stage 1 (52.5%)72.7 % 65.6 %Peak Stage 2 (16.4%)11.4 %Peak Stage 3 (31.2%)15.9 % 44.4 %S. Piano et al. (J. Hepatol. 2013 ; in press)Resolution62.5 % 36.8 %40 %Renal failure in cirrhosis
  15. 15. %020406080100sCr < 1.5 mg/dl sCr > 1.5 mg/dl-Probability of AKIN 1 stage regression accordind to the cut offof 1.5 of serum creatinine (sCr)S. Piano et al. (J. Hepatol. 2013 ; in press)p < 0.01Renal failure in cirrhosis
  16. 16. Proposal of an algorithm for AKI managementWithdrawal of diuretics (if notyet applied) and volumeexpansion with albumin(1g/kg) for 2 daysInitial AKI# stage 1 and sCr ≥ 1.5mg/dl° or initial AKI# stage > 1Initial AKI# stage 1 and sCr < 1.5mg/dl°° = sCr at the first fulfilling of AKIN crieria#= AKI at the first fulfilling of AKIN crieria* Treatment of SBP includes albumin infusionClose monitoringRemove risk factors (withdrawal of nephrotoxicdrugs, vasodilators and NSADs, taper/withdrawdiuretics treat infections*when diagnosed)Progression ?NOClose follow upYESResponse ?YES NODoes AKI Meet criteria of HRS ?Specific treatment forother AKI phenotypesNOTerlipressin andalbuminYESS. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  17. 17. • The acceptance of the main point that derived from theapplication of AKIN criteria that is to focus attention on andto manage promptly even small increases in sCr.• A clear dinstinction between AKI and hepatorenalsyndrome (which is only one of the possible phenotypes ofAKI)• A more rationale application of the therapeutic resources(avoiding of potentially dangerous consequences of anovertreatment of AKI as a consequence of an uncriticalapplication of the AKIN criteria)• The definitive removal of any cut off of serum creatininefrom the criteria for diagnosis of HRSClinical consequences of our proposal of an algorithmfor AKI managementS. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  18. 18. Proposal of an algorithm for AKI managementWithdrawal of diuretics (if notyet applied) and volumeexpansion with albumin(1g/kg) for 2 daysInitial AKI# stage 1 and sCr ≥ 1.5mg/dl° or initial AKI# stage > 1Initial AKI# stage 1 and sCr < 1.5mg/dl°° = sCr at the first fulfilling of AKIN crieria#= AKI at the first fulfilling of AKIN crieria* Treatment of SBP includes albumin infusionClose monitoringRemove risk factors (withdrawal of nephrotoxicdrugs, vasodilators and NSADs, taper/withdrawdiuretics treat infections*when diagnosed)Progression ?NOClose follow upYESResponse ?YES NODoes AKI Meet criteria of HRS ?Specific treatment forother AKI phenotypesNOTerlipressin andalbuminYESS. Piano et al. (J. Hepatol. 2013 ; in press)Renal failure in cirrhosis
  19. 19. Hepatorenal syndrome (HRS)Treatment of HRS
  20. 20. Pharmacologic therapy for HRS• Albumin (20-40 g/day intravenously)• Terlipressin (0.5-2 mg/4-6hr intravenously)J. Uriz et al. J. Hepatol. 2000 ; 33 : 43-48.Hepatorenal syndrome (HRS)
  21. 21. Hepatorenal syndrome (HRS)020406080100Noradrenalin TerlipressinP. Sharma et al. Am. J. Gastroenterol. 2008 ; 103:1689–1697.Percent of responders after at day 15P = N.S.50 % 40 %
  22. 22. Hepatorenal syndrome (HRS)Cumulative probability of survival during therapy of patients treatedwith noradrenaline and terlipressinV. Singh et al. J. Hepatol. 2012 ; 56 : 1293–1298
  23. 23. Hepatorenal syndrome (HRS)050010001500200025003000Noradrenalin TerlipressinP. Sharma et al. Am. J. Gastroenterol. 2008 ; 103:1689–1697.Cost of treatment in USD excluding that of albuminP < 0.056 mg/day for15 days1.5 mg/h for15 days
  24. 24. Patients with response to treatmentHepatorenal syndrome (HRS)020406080100Group A (Terlipressin) Group B (Midodrine + Octreotide)All responders Full responders% P < 0.0175.025.0P < 0.0154.28.3M. Cavallin et. al. (manuscript in preparation)
  25. 25. Pharmacologic therapy for HRS• Albumin (20-40 g/day intravenously)• Terlipressin (0.5-2 mg/4-6hr intravenously)J. Uriz et al. J. Hepatol. 2000 ; 33 : 43-48.Hepatorenal syndrome (HRS)
  26. 26. The facts• Vasoconstrictors and albumin are effective inless of 50 % of patients with type 1 HRS.• Vasoconstrictor and albumin improve survivalslightly.• Vasoconsctrictors and albumin can not beused in all patients with type 1 HRS.• In up to 25 % of patients the treatment shouldbe discontinued for adverse effects.• High cost of treatment.Hepatorenal syndrome (HRS)P. Angeli et al. Liver Int. 2012 (Epub ahead of print)
  27. 27. Limitations of terlipressin plus albumin• Inherent• ExtrinsicHepatorenal syndrome (HRS)
  28. 28. HRS is a functional renal failure caused by intrarenalvasoconstriction which occurs in patients with end stage liverdisease as well as in patients with acute liver failure or alcoholichepatitis.HRS is characterized by impaired renal function, markedalterations in cardiovascular function, and overactivity in theendogenous vasoactive systems.Hepatorenal syndrome (HRS)Definition of HRSF. Salerno et al. Gut 2007 ; 56 : 1310-1318.
  29. 29. CKD AKISerum creatinine > 1.5 mg/dl for ≥ 3 months/type 2 HRS* /type 1 HRS** Proteinuria < 0.5 g/l and no hematuriaHepatorenal syndrome (HRS)JM. Trawale et al. Liver Int. 2010 ; 30 : 725-732.
  30. 30. Serum creatinine levels >1.5 mg/dlProteinuria > 0.5 g/day Haematuria182095427JM. Trawale et al. Liver Int. 2010 ; 30 : 725-732.Hepatorenal syndrome (HRS)
  31. 31. Renal vascular injuryAcutetubulointerstitialinjuryChronictubulointerstitialinjury10 (18)13 (18)12 (18)JM. Trawale et al. Liver Int. 2010 ; 30 : 725-732.Hepatorenal syndrome (HRS)
  32. 32. 0100200300400no HRS HRSNGAL urinary levels in patients with cirrhosis andascites according to the diagnosis of type 1 HRSM. Cavallin at al. AASLD 2011P < 0.025(ng/ml)Hepatorenal syndrome (HRS)Instrinsic AKI****** ***************** *E. Singer et al. Kidney Int. 2011 ; 80 : 405-414
  33. 33. 0100200300400500Full responders Partial or non respondersp < 0.0025M. Cavallin. et. al. AASLD 2011NGAL urinary levels in patients with type 1 HRSaccording to the response to terlipressin and albumin(ng/ml)Hepatorenal syndrome (HRS)
  34. 34. The ratio of urinary excretion of γ-glutamyltranspeptidaseto glomerular filtration rate in patients with type 1 HRStreated with vasonsctrictors and albumin0100200300400500* = P < 0.05 ; ** = P < 0.025****B D5 D10 B D5 D10Nonresponders RespondersD20P. Angeli et al. Hepatology 1999 ; 29 : 1690-1697.Normal rangeHepatorenal syndrome (HRS)
  35. 35. Peripheral arterial vasodilation “hypothesis”Portal hypertension/liver failureReduction of effective circulating volumeSevere renal arterial vasoconstrictionMaximal activation ofendogenous vasocontrictor systemsRW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157 (revised)Increased release of NO, COand other vasodilatorsSplanchnic arterial vasodilationTerlipressinAlbuminHepatorenal syndrome (HRS)
  36. 36. Hepatorenal syndrome (HRS)HRS after SBPresolutionNo HRS after SBPresolutionPMAP (mm Hg) 73±8 83±8 < 0.025SVR (dyn sec/cm ) 1268±320 968±226 N.S.Plasma NE (pg/ml) 1290.5±415.3 317.±195.3 <.025CO (l/min) 4.6±0.7 6.8±2.0 < 0.01RAP (mm Hg) 4.6±2.7 4.1±1.7 N.S.PCWP (mm Hg) 7.4 ±2.6 7.0±2.3 N.S.HR (bpm) 87±9 79±16 N.S.5Systemic heamodynamics before and after the onset of HRS after theresolution of SBPL. Ruiz-del-Arbol et. al. Hepatology 2003 ; 38 : 1210-1218
  37. 37. BaselineAt the diagnosis ofHRSPMAP (mm Hg) 80±975±7< 0.001HVPG (mm Hg) 19.5±3.020.0±4.0< 0.005SVR (dyn sec/cm ) 1158±285 1096±327 N.S.CO (l/min) 6.0±1.2 5.4±1.3 < 0.001RAP (mm Hg) 6.9±2.65.7±2.2< 0.05PCWP (mm Hg) 9.2 ±2.67.5±2.6< 0.001Systemic heamodynamics before and after the onset of type 1 HRS inpatients with cirrhosis and ascites without a precipitating factorL. Ruiz-del-Arbol et. al. Hepatology 2005 ; 62 : 439-447.5Hepatorenal syndrome (HRS)
  38. 38. Peripheral arterial vasodilation “hypothesis” (revised)Portal hypertension/liver failureReduction of effective circulating volumeSevere renal arterial vasoconstrictionMaximal activation ofendogenous vasocontrictor systemsRW. Schrier et al. Hepatology 1988 ; 8 : 1151-1157 (revised)Increased release of NO, COand other vasodilatorsSplanchnic arterial vasodilation Reduced cardiac output?Hepatorenal syndrome (HRS)
  39. 39. Hepatorenal syndrome (HRS)Y. Narahara et al. J. Gastroenterol. Hepatol. 2009 ; 24 : 1791-1797Parameter BaselineAfterterlipressinPHeart rate (bpm) 83 ± 16 72 ± 16 < 0.005Mean arterial pressure (mm Hg) 89 ± 11 105 ± 14 < 0.005Systemic vascular resistance (dynes/s · cm5) 1295 ±293 1653 ± 465 < 0.005Cardiac output (l/min) 5.2 ± 1.0 4.9 ± 1.1 < 0.05Pulmunary capillary wedged pressure(mm Hg)9.6 ± 3.1 12.3 ± 2.6 < 0.005Systemic hemodynamics at baseline and 30 min. after terlipressin in patientswith cirrhosis and ascites
  40. 40. Hepatorenal syndrome (HRS)ParameterContrlsubjects(n° = 46)Patients withcirrhosis andwithoutascites (n° =36)Patients withcirrhosis andresponsiveascites(n° = 31)Patients withcirrhosis andrefractoryascites(n° = 46)Heart rate (beat/min) 67±10 70±10 68±11 78±13*#Mean arterial pressure(mm Hg)97±7 99±10 96±11 87±9*##Systemic vasciularresistance (din s/cm5m2)3371±648 2925±641*** 2860±776*** 2439±573***#Stroke volume (ml/beat) 64±10 75±12** 77±11** 73±17**Cardiac output (L/min) 4.27±0.80 5.28±1.11*** 5.29±1.42*** 5.60±1.50***Systemic hemaodynamics according to the stage of cirrhosis* = p < 0.01 ; ** = p < 0.001 ; *** = p < 0.001 versus control subjects ; # = p < 0.05 ; ## = < 0.001 versusother groups of patients with cirrhosisM. Cesari et al. (manuscript submitted)
  41. 41. Cardiac output in cirrhotic patients according to the Child-Pugh-Turcotte class3000600090001200015000Class A Class B Class CBasal After i.v. albumin (40 g)K. Brinch et al. J. Hepatol. 2003 ; 39 : 24-31* = P < 0.025* *(ml/min)* ** * = P < 0.01Hepatorenal syndrome (HRS)
  42. 42. 05101520P < 0.005Overall transvascular transport of albumin incirrhosisJ. H. Henriksen et al. J. Hepatol. 2001 ; 34 : 53-60.Controls Cirrhoticswith ascitesCirrhoticswith refractory ascitesP < 0.01(% IVM • h )-1Hepatorenal syndrome (HRS)
  43. 43. Effects of albumin on cardiac contractility in cirrhotic rats-10.0 -9.5 -9.0 -8.5 -8.00510152025∆LVDP(mmHg)ControlCirrhoticLog . IsoproterenolCirrhotic + albumin* = P < 0.01**Cirrhotic + starchHepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  44. 44. ?Hepatorenal syndrome (HRS)
  45. 45. NAD(P)H•p67p47gp91rac•O2-O2 H+NAD(P)+p22phoxNADH/NADPH OxidaseThe NADPH/NADH oxidaseHepatorenal syndrome (HRS)
  46. 46. 00,511,52control rats treated with V control rats treated with Arats with cirrhosis treated with V rats with cirrhosis treated with AMembrane/cytosolratio(foldofincrease)*p <0.05 vs controls ; # = p <0.05 vs rats with cirrhosistreated with V*#p47-phox Rac-1*#Effects of albumin on the NADH/NADPH oxidase in the cardiactissue according to treatment with saline (V) or albumin (A)Hepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  47. 47. ?TNF-αHepatorenal syndrome (HRS)
  48. 48. 00,20,40,60,811,21,41,61,8Control rats treatedwith VControl rats treatedwith ARats with cirrhosistreated with VRats with cirrhosistreated with AFoldofincrease*#* p<0.05 vs control rats # p<0.05 vs rats with cirrhosis treated with VLevels of NF-kB traslocation in the cardiac tissue according totreatment with saline (V) or with albumin (A)Hepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  49. 49. Proteinexpression(foldofincrease)*#* p<0.05 vs controlsEffects of albumin on TNF-α protein expression in the cardiactissue according to treatment with saline (S) or albumin (A)# p<0.05 vs rats with cirrhosis treated with A00,511,522,5Control rats treatedwith SControl rats treatedwith ARats with cirrhosistreated with SRats with cirrhosistreated with AHepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  50. 50. Proteinexpression(foldofincrease)*#* p<0.05 vs controlsEffects of albumin on iNos protein expression in the cardiactissue according to treatment with saline (S) or albumin (A)# p<0.05 vs rats with cirrhosis treated with A00,511,522,5Control rats treatedwith SControl rats treatedwith ARats with cirrhosistreated with SRats with cirrhosistreated with AHepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  51. 51. TNF-αHepatorenal syndrome (HRS)
  52. 52. ?Hepatorenal syndrome (HRS)
  53. 53. * = p < 0.01 vs controllEffects of albumin on β-adgrenergic signaling in cardiac tissue according totreatement with saline (V) or albumin (A)00,511,522,5β1 β2 Adcy3 Gαi2control rats treated with V control rats treated with Arats with cirrhosis treated with V rats with cirrhosis treated with A****# #* p<0.05 vs controls ; # p<0.05 vs ascites with salineGeneexpression(Foldofincrease)**Hepatorenal syndrome (HRS)A. Bortoluzzi et al. Hepatology 2013 ; 57 : 266-276
  54. 54. Hepatorenal syndrome (HRS)
  55. 55. Limitations of terlipressin plus albumin• Inherent• ExtrinsicHepatorenal syndrome (HRS)
  56. 56. Response to tretament (%) according to the baseline serumcreatinine value01020304050603.0 mg/dl < 3 - 5 mg/dl > 5.0 mg/dlTD. Boyer et al. J. Hepatol. 2011 ; 55 ; 315-321.%MANAGEMENT OF RENAL DYSFUNCTION IN PATIENTS WITH CIRRHOSIS
  57. 57. Summary• The application of conventional criterion is more accurate than a formalapplication of AKIN criteria in the prediction of in-hospital mortality inpatients with cirrhosis and ascites.• Nevertheless, the addition of either the progression of AKIN stage or the cut-off of serum creatinine ≥1.5 mg/dl, to the AKIN improves their prognosticaccuracy in these patients .• The potential effects of implementation of the conventional criterion with themost innnovative aspects of AKIN criteria, should be tested by interventionalclinical trials in the next future.• Terlipressin and albumin are effective in patients with type 1 HRS.• Noradrenalin and albumin but not midodrine, octreotide and albumin canrepresent an alternative in the treatment of type 1 HRS.• Some of the limits of the treatment with terlipressin and albumin may berelated to the fact that HRS may not be completely functional in natureand/or to the fact that the global effect of the treatment on cardiac outputmay be negative in some patients.Hepatorenal syndrome (HRS)P. Angeli et al. Liver Int. 2013 ; 33 : 16-23

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