Vasoconstrictor Therapy in Hepatorenal Syndrome: When to Use it and How

Transcription

1 KidneyCon Little Rock, AR, April 7 th, 2018 Vasoconstrictor Therapy in Hepatorenal Syndrome: When to Use it and How Juan Carlos Q. Velez, MD Associate Professor of Medicine, Ochsner Clinical School / The University of Queensland Interim Chair, Department of Nephrology, Ochsner Clinic Foundation

2 Outline When to Use Vasoconstrictor Therapy Challenges of diagnosing hepatorenal syndrome type 1 (HRS-1) in clinical grounds Risk factors, definition, pathogenesis, confounders How to Use Vasoconstrictor Therapy Evidence supporting the use of vasoconstrictors in HRS-1 The importance of a mean arterial pressure (MAP) target in HRS-1 management

3 Ann Int Med, 1959 n = 22 ESLD ü ü ü SBP mmhg T Bili mg/dl SNa meq/l GI Bleeding Progressive Jaundice Paracentesis None Serum Cr mg/dl AKI 100% Died Hepatic Coma ü ü ü bland, hyaline occasional granular casts Trace protein, blood 18/22 (82%) ü ü Essentially normal Minimal tubular flattening, bile staining

4 HRS-1 Diagnosis: Most Common Precipitating Events: Spontaneous Bacterial Peritonitis (SBP) and Gastrointestinal (GI) Bleeding % n = /252 (33%) % % 13/27 n = 68 (48%) 50 10/23 n = n = 27 (43%) 9/27 (33%) 7/27 4/23 (27%) 25 (17%) 25 SBP Follo A et al (Hepatology 1994) SBP prophylaxis prevents HRS Fernandez J et al (Gastroenterology 2007) SBP GI Bleeding Hampel H et al Am J Gastro 2001) Bacterial Infection GI Bleeding Watt K et al (Am J Gastro 2002) LV Paracentesis

5 HRS-1 Diagnosis: Revised 2015 Definition by the International Club of Ascites Incorrect adjudication of HRS-1 Dx 100 CVP 8 mmhg? IVC diameter? 50 27/46 (59 %) 27/73 (37 %) Watt K et al (Am J Gastro 2002) Velez JC et al (Nephron 2015) Wong F & Angeli P (J Hepatology 2016) Angeli P et al (Gut 2015) Low BP normal for cirrhotics? antibiotics? RBCs/hpf? Foley? chronic IgA GN? Granular casts, RTECs, WBCs? IAP < 25 mmhg? UNa < 20 meq/l?

6 HRS-1 Diagnosis: Standard 48 hr. Volume Challenge May Not Apply to All Patients POCE-based Volume Assessment in Hepatorenal AKI Clinical diagnosis of HRS-1 (n = 53) ü IVC diameter by US, IVC % collapsibility IVC < 1.3 cm (n = 23) IVC cm (n = 17) IVC > 2.0 cm (n = 13) Collapsibility > 40% (n = 15) Collapsibility < 40% (n = 8) Deemed Euvolemic HRS-1 confirmed (n = 17) Collapsibility > 40% (n = 2) Collapsibility < 40% (n = 11) Category: Volume Depletion 100% Volume Expanded 67% Responded (n = 10) Category: IAH 75% LVP 50% Responded (n = 3) Deemed Euvolemic HRS-1 confirmed (n = 2) Category: Volume Overload 100% Loop Diuretics 63% Responded (n = 7) Huggins T et al, MUSC, unpublished data Velez et al, Kidney Week 2018, SA-OR102

7 HRS-1 Diagnosis: FENa < 1% is always present but not diagnostic n = 88 FENa < 1% to diagnose HRS FENa according to biopsy-proven diagnosis Alsaad & Wadei et al (World J Hepatol 2016)

8 HRS-1 Diagnosis: Cardiorenal Syndrome May Overlap with HRS-1 Porto-Pulmonary Hypertension High-Output Heart Failure Cirrhotic Cardiomyopathy Zardi EM et al Zardi EM et al (Eur J Int Med 2017) (J Cardiol 2015) Krag et al (Gut 2010)

9 Confounder for HRS-1? Bile Cast Nephropathy (Cholemic Nephrosis) Biliary obstruction (cholangioca, stricture) Drug-induced hepatitis Acute alcoholic/viral hepatitis Sequeira et al. Hemodial Int 2015 Aniort et al. AJKD 2017 Tabatabaee et al. lran J Kidney 2015 What about in cirrhosis? Autopsy / postmortem biopsy studies T. Bilirubin: mg/dl HRS - AKI No HRS ACLF ESLD HRS 0 Foshat et al. Am J Clin Pathol Bile Cast Nephropathy Bile Cast Nephropathy NO Bile Cast Nephropathy NO Bile Cast Nephropathy Van Slambrouck et al. Kidney Int 2013 Nayak et al. J Clin Transl Hepatol

10 HRS-1 Diagnosis: Urine Microscopy in Hepatorenal AKI Bland / hyaline casts Bili-stained RTEC casts Bili-stained casts True granular casts Cast with leucine crystals Bilirubin crystals

11 Proposed Model for Progression to Tubular Injury in HRS-1 Strictly Functional AKI Tubular Stasis Tubular Stasis Progression to Ischemia Progression to Ischemia / Bile Intrinsic Tubular Injury

12 Acute Kidney Injury in Acute Liver Failure due to Acetaminophen Toxicity is NOT a form of HRS-1 Toxic Acute Tubular Injury Cultured Proximal Tubular Epithelial Cells: Pyknotic Nuclei Lorz C et al (JASN 2004)

13 Summary (1) Diagnosis of HRS is challenging and requires careful clinical evaluation. Clinical picture often cloudier than desired No test for definite diagnosis HRS-1 and intrinsic kidney damage may coexist (so-called HRS physiology ) or HRS-1 and CKD (HRS type 3) 1 or HRS-1 and ATI (? HRS type 4) 1. Rajekar & Chawla. India. J Gastroenterol Hepatol 2011

14 Why Should We Treat HRS-1? What do we accomplish if HRS is successfully treated with vasoconstrictors? 3-month transplant-free survival n = 99 Transplanted: 97% (34/35) Responders 41% (7/17) Non-responders 4% (2/47) 1. Boyer T et al. Terlipressin Study Group. Liver Transplantation Heidemann et al. Germany. Gastroenterol Res Pract 2015.

15 Vasoconstrictor Therapy in HRS-1 Dopamine Midodrine / Octreotide Ornipressin Vasopressin Terlipressin Norepinephrine

16 Vasoconstrictor Therapy in HRS-1 Dopamine Midodrine / Octreotide Ornipressin Vasopressin Terlipressin Norepinephrine

17 Vasoconstrictor Therapy in HRS-1 Midodrine + Octreotide vs. Dopamine Prospective Non-Parallel Trial ESLD + HRS Dopamine 2-4 µg/kg/min IV n = 13 (n = 8) (n = 5) ü serum Cr (mg/dl) 3.5 ± ± 0.4 ü MAP (mmhg) 76 ± 3 78 ± 4 ü T Bili (mg/dl ü serum Na (meq/l) Midodrine / Octreotide mg po tid µg sq tid Angeli et al (Hepatology 1999) Albumin IV: g IV + add g IV if CVP < 12 or < 50% PRA by day 3 Serum Cr or UOP Rise in MAP 15 mmhg

18 Vasoconstrictor Therapy in HRS-1 Midodrine + Octreotide vs. Dopamine Prospective Non-Parallel Trial Angeli et al (Hepatology 1999) % improved scr by day Midodrine/Octreotide (n = 5) Dopamine (n = 8) 60 % mmhg mean MAP 16 mmhg 0 % 40 Day 1 Day 5 Day 10

19 Vasoconstrictor Therapy in HRS-1 Dopamine Midodrine / Octreotide Ornipressin Vasopressin Terlipressin (V1a:V2 = 2.2:1) Norepinephrine

20 Vasoconstrictor Therapy in HRS-1 Terlipressin vs. Placebo Randomized Controlled Trial n = 104 Sanyal A et al n = 196 (Gastroenterology 2008) Terlipressin vs. Placebo Randomized Controlled Trial (REVERSE) Boyer T et al (Gastroenterology 2016) Terlipressin Placebo TS = treatment success = HRS reversal for 48 hrs % 50 p = % 50 p = % 12.5 % % 13 %

21 Vasoconstrictor Therapy in HRS-1: Terlipressin (CONFIRM Trial)

22 Vasoconstrictor Therapy in HRS-1: Raising the Mean Arterial Pressure Terlipressin Responded to Terlipressin Did NOT Resp to Terlipressin p < 0.01 Placebo mean MAP rise (mmhg) Boyer T et al. (J Hepatol 2011) Boyer T et al (Gastroenterology 2016)

23 Vasoconstrictor Therapy in HRS-1: Terlipressin vs. Midodrine/Octreotide Randomized Controlled Trial p = 0.01 n = 48 Terlipressin Midodrine/Octreotide Cavallin et al (Hepatology 2015) HRS Reversal (%) % 28 % MAP by day 3 (mmhg) p =

24 Vasoconstrictor Therapy in HRS-1 Dopamine Midodrine / Octreotide Ornipressin Vasopressin Terlipressin Norepinephrine

25 Vasoconstrictor Therapy in HRS-1 Norepinephrine Duvuox et al (Hepatology 2002) Pilot study scr (µmol/l) ESLD + HRS n = 12 ü serum Cr (mg/dl) 4.0 ± 0.8 ü MAP (mmhg) 65 ± 3 ü T Bili (mg/dl) 16.5 ü Child-Pugh score 11.3 Norepinephrine 3 20 µg/min IV Target 10 mmhg MAP Mean MAP (mmhg) d3

26 Vasoconstrictor Therapy in HRS-1 Norepinephrine vs. Terlipressin Sharma et al. (Am J Gastroenterol 2008) Singh et al. (J Hepatol 2012) 100 n = n = 46 % HRS Reversal % 50 % Mean MAP (mmhg) % HRS Reversal % 39 % Mean MAP (mmhg) d 8d 40 0 d15

27 501 patients-data

28 Vasoconstrictor Therapy in HRS-1: Raising the Mean Arterial Pressure Velez JC & Nietert PJ (Am K Kidney Dis 2011)

29 mmhg Vasoconstrictor Therapy in HRS-1: Meta-Analysis of 21 Studies Baseline MAP 37 cohorts Mean: 74.6 mmhg Median: 76 mmhg Velez JC & Nietert PJ (Am K Kidney Dis 2011)

30 Change in SCr from Baseline Hepatorenal AKI and the Importance of Raising the MAP Quartile 1 (-9.0 to +0.0 mmhg) True HRS-1 Subjects (n = 27) Quartile 2 (+0.8 to +4.9 mmhg) Quartile 3 (+5.3 to mmhg) Multivariate mixed liner regression model p = Quartile 4 (+15.9 to mmhg) Velez JC et al (Nephron 2015)

31 n = 14 Norepinephrine as Rescue Therapy from Midodrine/Octreotide in HRS-1 Attention to MAP Rise Velez JC et al (Nephron 2015)

32 Vasoconstrictor Therapy in HRS-1: Raising MAP Renal Blood Flow Autoregulation Curve is Shifted in ESLD Role of Sympathetic Nervous System Activation Rat model of AKI due to renal vasoconstriction control Dog model of AKI due to SNS activation ~ 62 mmhg Human study in cirrhotics (n = 56) RBF AKI MAP ~ 91 mmhg HRS-2 Kelleher S et al (Am J Physiol 1984) Persson P et al (Am J Physiol 1999) Stadlbauer V et al (Gastroenterology 1999)

33 Summary (2) Vasoconstrictor therapy (w/albumin) for 3 days may improve kidney function in % of HRS cases Standard practice in USA of using midodrine/octreotide is not supported by solid evidence. Norepinephrine seems a valid, perhaps better alternative Reversal of HRS with vasoconstrictor therapy without a substantial rise in MAP has not been reported Targeting a rise in MAP (~ mmhg; ~ goal 85 mmhg) appears reasonable as HRS-1 treatment target, but prospective controlled studies are needed to verify its safety and efficacy

34 Case Example yo man T Bili (mg/dl) Biliary tube exchange / IVF (NS) v Primary Sclerosing Cholangitis - ESLD v Baseline scr 1.1 RFA: worsening jaundice ü BP 121/66 mmhg scr (mg/dl) MAP (mmhg) OLT ü sna 138; una day

35 Case Example yo man T Bili (mg/dl) LVEF 35% Leukocytosis v Alcoholic, Fatty - ESLD v Baseline scr 1.0 RFA: ACLF, ETOH intoxication scr (mg/dl) ü BP 135/64 mmhg ü sna 132; una < 20 MAP (mmhg) day

36 Case Example yo man T Bili (mg/dl) IV albumin Midodrine / Octreotide 3.8 IV norepinephrine RHC: PAP 55 PCWP 21 IV furosemide v HCV - ESLD v Baseline scr 1.3 v Pulmonary HTN scr (mg/dl) RFA: worsening ascites, evaluation for HCC ü BP 92/53 mmhg MAP (mmhg) ü sna 134; una < day UOP 1 L/d

37 Approach to Cirrhosis + AKI stage 2 scr >50 RBCs >10 WBCs UPCR >>1.0 U Na > 40 Shock, BP Volume Expansion 1-3 days: IV Albumin Spectrum equivocal scr course urine findings +/- drug confounders Renal US/CKD/Echoc scr (-) RBCs (-) WBCs (-) Prot U Na < 10 NOT HRS-1 Possible HRS-1 Definite HRS-1 MAP<75, sna<135, oliguria Improbable HRS-1 Probable HRS-1 DO NOT Initiate Vasoconstrictor therapy for HRS-1 Initiate Vasoconstrictor therapy + IV Albumin AKI stage 2 AKI stage 3 Repeat if Recurrence Midodrine PO / Octreotide SQ or Norepinephrine IV Target MAP rise 15 mmhg Response Treat 3-7 days, switch/continue Midodrine PO / Octreotide SQ No Response Norepinephrine IV Target MAP rise 15 mmhg or MAP 85 mmhg No Response in 2-3 days STOP

38 Conclusions HRS-1 represents a diagnostic challenge because of the lack of gold-standard, the complexity of the clinical scenarios and the severity of the disease Vasoconstrictor therapy on HRS-1 targeted to raising the MAP is associated with improvement in kidney