Presentazione di PowerPoint · Hepatorenal syndrome P. Angeli, Dept. of Medicine, Unit of Internal...

Hepatorenal syndrome

P. Angeli, Dept. of Medicine, Unit of Internal Medicine and Hepatology (UIMH),

University of Padova (Italy)[email protected]

UIMH

37th Vicenza Course on AKI & CRRTVicenza (Italy) May 28-30th, 2019

Disclosures

•2014- 2018: Sequana Medical AG Advisory Board

•2016-2018: Biovie Advisory Board and patent application

•2016: Gilead (Italy): Advisory Board and grant

•2014-2018: Bhering: speaker invitation and travel grant

•2016: Kedrion speaker invitation

•2018: Ferring: Advisory Board

2019

MANAGEMENT OF PATIENTS WITH CIRRHOSIS

UIMH

0

20

40

60

80

100

AKI AKI+CKD CKD

N.S. Warner et al. J. Investig. Med. 2011 ; 59 : 1244-1251.

Prevalence of AKI and CKD in patients with cirrhosis admitted to the hospital

%

70 %

17 %13 %

2019


UIMH

Definition and staging of Acute Kidney Injury (AKI)

KDIGO AKI Work Group Kidney Int. Suppl. 2012 ; 2 : 1-138

KDIGO criteria = an abrupt (within 48 hours) reduction in kidney function currently definedas an absolute increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4μmol/l), or a percentage increase in serum creatinine of more or equal to 50 % (1.5-fold frombaseline) in less than 7 days.

Stage Serum creatinine criteria

1°Increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4μmol/l) or a percentage increase in serum creatinine of more or equal to 50 %(< 2 fold from baseline).

2°Increase in serum creatinine to more than 200% to 300% (> 2- to 3-fold) from baseline

3°

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 replacementtherapy

2019


UIMH

Criteria Sensibility95 % CI

Specificity95% CI

PPV95% CI

NPV95% CI

LR+95% CI

LR-95% CI

Conventional criteria 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)

KDIGO 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)

KDIGO withProgression

0.5455(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 KDIGO criteria in the prediction of in-hospital mortality in a series of 233 patients with cirrhosis and ascites

S. Piano et al. J. Hepatol. 2013 ; 59 : 482-489

2019


UIMH

P <0.001

P <0.0001

P <0.0001

P=N.S.P <0.025

P <0.01

Initial AKI stage≠ and in-hospital mortality

S. Piano et al. J. Hepatol. 2013 ; 59 : 482-489

%

0

20

40

60

80

100

No AKI AKI stage 1 AKI stage 2 AKI stage 3

# = AKI stage at the first fulfillement of KDIGO criteria

2019


UIMH

Survival of in hospitalized patients with cirrhosis according to Acute Kidney Injury (AKI).

C. Fagundes et al. J. Hepatol. 2013 ; 59 : 474–481# = with peak creatinine level <1.5 mg/dl, * = with peak creatinine level 1.5 mg/dl

2019


UIMH

Algorithm for AKI management in patients with cirrhosis

Initial AKI# stage ≥ 1aInitial AKI# stage 1a


Close monitoringRemove risk factors (withdrawal of nephrotoxic drugs,

vasodilators and NSADs, taper/withdraw diuretics, expand plasma volume, treat infections*when

diagnosed)

Resolution

Close follow up

P. Angeli et al. J. Hepatol. 2015 ; 62 : 968-974

Algorithm for AKI management in patients with cirrhosis

Initial AKI# stage > 1aInitial AKI# stage 1a

Close monitoringRemove risk factors (withdrawal of nephrotoxic drugs,

vasodilators and NSADs, taper/withdraw diuretics, expand plasma volume, treat infections*when

diagnosed)

Resolution

Close follow up

Response ?

NO

Does AKI meet criteria of HRS ?

Specific treatment for other AKI phenotypes

NO

Persistance

Further treatment of AKI decided on a

case-by-case basis

Withdrawal of diuretics (if notyet applied) and volume expansion with albumin

(1g/kg) for 2 days

Progression YES

P. Angeli et al. J. Hepatol. 2015 ; 62 : 968-974


vasoconstrictorsand albumin

YES

Definition and defining criteria of AKI in cirrhosis

P. Angeli et al. Gut 2015 ; 64 : 531-537

2019


UIMH

Prevalence of AKI on admission using an imputed value or a previous valueof serum creatinine (sCr)

p < 0.05

2017


UIMH

S. Rosi et al. Liver Int. 2015 ; 35 : 2108-2014

%

0

20

40

60

80

100

Imputed sCr Previous real sCr

Definition and staging of Acute Kidney Injury (AKI)


KDIGO urine output criteria = an urinary output < 0.5 ml/kg B.W./hr x 6-12 hours

Stage Serum creatinine criteria

1°an urinary output < 0.5 ml/kg B.W./hr x 6-12 hours

2°an urinary output < 0.5 ml/kg B.W./hr x 12 -24 hours

3°an urinary output < 0.5 ml/kg B.W./hr x 24 or more hours or anuria per 12 hr

2019


UIMH

AKI sCr + UO

2854 (82.5%)

AKI only sCr

2002 (57.9%)

AKI only UO

2553 (73.8%)

Patients

2997

Critically ill patients with cirrhosis and AKI diagnosed by KDIGO criteria

R. Amathhieu et al. Hepatology 2017 ; 66 : 1592-1600

2019


UIMH

One-year age-adjusted survival for patients with stage 3 AKI-sCr, AKI-UO or AKI-sCr+UO

R. Amathhieu et al. Hepatology 2017 ; 66 : 1592-1600

%

sCr only

UO only

sCr + UO

2019


UIMH

• Acute tubular necrosis (ATN-AKI) (41.7%)

• Prerenal failure (Prenal-AKI) (38%)

• Hepatorenal syndrome (HRS-AKI) (20%)

• Postrenal failure (Postrenal AKI) (0.3%)

Types of AKI in patients with cirrhosis and ascites

R. Moreau et al. Hepatology 2003 ; 37 : 233-243.

2019


UIMH

HRS is a functional renal failure caused by intrarenal vasoconstrictionwhich occurs in patients with end stage liver disease as well as inpatients with acute liver failure or alcoholic hepatitis.HRS is characterized by impaired renal function, marked alterations incardiovascular function, and overactivity in the endogenousvasoactive systems.

Definition of hepatorenal syndrome (HRS)

F. Salerno et al. Gut 2007 ; 56 : 1310-1318

2019


UIMH

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.

Current diagnostic criteria of HRS

F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

Deleted

2019


UIMH

Biomarkers No AKI Prerenal AKI HRS-AKI ATN-AKI P

NGAL (μg/g sCr) 30 (17-41) 36 (26-125) 104 (58-208) 1807 (494-3716) <0.0001

IL-18 (ng/g sCr) 21 (16-35) 16 (14-36) 18 (10-29) 150 (58-259) <0.0001

Albumin (mg/g sCr) 3 (1-7) 9 (1-77) 16 (8-46) 324 (53-380) <0.0001

TFF-3 (μg/g sCr) 582 (367-1665) 2300 (323-2720) 1893 (840-2715) 5810 (4019-14466) < 0.0001

MCP-1 (μg/g sCr) 0.2 (0.1-1.4) 0.9 (0.2-2.5) 3 (1-6) 4 (1-14) <0.0001

Ostepontin (μg/g sCr) 1456 (715-3210) 2914 (1847-8382) 5471 (2959-11983) 83337 (4019-14466) < 0.0001

Calbindin (μg/g sCr) 71 (26-150) 5 (2-34) 25 (8-58) 118 (37-324) 0.010

GST-TT (μg/g sCr) 3 (1-16) 3 (1-7) 4 (2-21) 50 (9-169) 0.012

KIM-1 (μg/g sCr) 0.5 (0.3-1.4) 0.5 (0.1-1.1) 1.2 (0.5-2.8) 1.7 (0.9-5.1) 0.015

Cistatin C (μg/g sCr) 24 (12-435) 21 (15-53) 27 (10-47) 115 (39-1552) 0.023

Values of urinary biomarkers in patients categorized according to the absence or presence of AKI and phenotype of AKI

X. Ariza et al. Plos One 2015 ; 10 [Epub ahead of print]

2019


UIMH

JM. Belcher et al. Hepatology 2014 ; 60 : 622-632

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5

PRE-AKI HRS-AKI ATN-AKI

Percentage of patients with prerenal- (PRE-), hepatorenal syndrome (HRS-), and acute tubular necrosis- (ATN-) AKI by the number of biomarkers of structural

injury above their optimal cutoff for the diagnosis of ATN

2019


UIMH

20

J. Puthumana, et al. Clin. Gastroenterol. Hepatol. 2017 : 15 : 1003-1013.

Sensitivity and specificity and AUROC of urine IL18 and urine NGAL for diagnosis of ATN

Biomarker Sensitivity Specificity AUROC

IL-18 0.80 (0.59-092) 0.88 (0.82-0.93) 0.88 (0.79-0.97)

NGAL 0.86 (0.68-094) 0.82 (0.75-087) 0.89 (0.84-0.94)

2019


UIMH

21

P. Huelin et al. J. Hepatol. 2017 ; 66 : S10-S11 (Abstract).

Urinary NGAL values in patients with cirrhosis and hepatorenal syndrome (HRS-), and acute tubular necrosis- (ATN-) AKI

0

200

400

600

800

1000

1200

1400

1600

ATN-AKI HRS-AKI

μg

/g c

reat

inin

e

2019


UIMH

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.

2019


UIMH

Rate of response in patients with type 1 HRS according to the schedule of i.v. administration of terlipressin

55,88

45,95

20,59 18,9

0

20

40

60

80

100

I.V. Continuous Infusion I.V. Boluses

Complete response Partial response

% P = N.S.

M. Cavallin et. al. 2016 ; 63 : 983-992

2019


UIMH

Peripheral arterial vasodilation “hypothesis”

Maximal activation of endogenous vasoconstrictor systems

Severe renal arterial vasoconstriction

RW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157

Maximal reduction of effective circulating volume

Terlipressin

Albumin

Portal hypertension/liver failure

Splanchnic arterial vasodilation

Increased release of NO, CO and other vasodilators

2019


UIMH

Cardiac dysfunctionSplanchnic vasodilation

Inflammatory/Oxidative state

Reduction of effective circulating volume

Activation of endogenous vasoconstrictorand sodium retaining factors

Ascites

Adapted from M. Bernardi et al. J. Hepatol. 2015 ; 63 : 1272 - 1284

New pathophysiological hypothesis

Other mechanisms?

Organ failures

PF

Portal hypertension/liver failure

Bacterial translocation

2019


UIMH

Renal hypoperfusion

Mechanisms of renal injury potentially involved in AKI in patients with liverdisease

2019


UIMH

Renal hypoperfusion

Microvascular dysfunction


2019


UIMH

Microvascular dysfunction in sepsis

0

10

20

30

40

50

60

70

80

90

Saline LPS LPS+L-Nil LPS+Z-VAD

0

5

10

15

20

25

30

Saline LPS LPS+L-Nil LPS+Z-VAD

Peritubular vessels with continuousflow (% vessels per 200 μ)

Peritubular vessels with no flow (% vessels per 200 μ)

< 0.01< 0.01

M.M. Tiwari et al. Am. J. Physiol., Renal Physyol. 2005 ; 289 : F1324-F1332).

2019


UIMH

Direct tubular damage

Mechanisms of renal injury potentially involved in AKI in patients with ALF

2019


UIMH

CM. Van Slambrouk et al. Kidney Int. 2013 ; 84 : 192-197.

Presence of tubular bile casts in patients with AKI and HRS

Patients(% of total)

Bile castspresent

Bile castsabsent

Patients with jaudice not due to cirrhosis

21(48%) 10 (48%) 11 (52%)

Patients with AKI 32 (73%) 21 (66%) 11 (44%)

Patients with cirrhosis 23 (52%) 14 (61%) 9 (39%)

Patients with cirrhosis and HRS

10 (23%) 10 (100%) 0 (0%)

2019


UIMH

Mechanisms of renal injury potentially involved in AKI in patients with ALF

Dangersignal/Inflammation

2019


UIMH

Endotoxin uptake in S1 segments of WT mice and TLR4 KO mice

R. Kalakeche et al. J. Am. Soc. Nephrol. 2011 ; 22 : 1505-1516

2019


UIMH

Volcano plots and Cleveland plots in the analysis of blood metabolites

2019

Acute on chronic liver failure

UIMH

J. Claria et al. 2019 ; (manuscript submitted)

Channeling of intracellular glucose in Acute on Chronic Liver Failure

2019


UIMH


Fatty aylcarnitines accumulation in patients with ACLF

2019


UIMH


Renal hypoperfusion

Direct tubular damage

Dangersignal/Inflammation

Microvascular dysfunction


2019


UIMH

Inflammation in patients with ACLF

* p<0.05 with respect to No ACLF

** p<0.001 with respect to No ACLF

C-reactive Protein

R. Moreau et al. Gastroenterology 2013 ; 144 : 1426-1437

0

10

20

30

40

50

60

70

No ACLF ACLF grade 1 ACLF grade 2 ACLF grade 3

***

**

2019


UIMH

Impact of ACLF grade on the rate of response to treatment with terlipressin plus albumin in patients with type 1 HRS

S. Piano et al. Clin. Gastroeterol. Hepato.. 2018 ; (Epub ahead of print)

2019


UIMH

Clinical types of HRS

Type 1 HRS : rapidly progressive reduction of renal function asdefined 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 mayoccurs spontaneously, but it can also follow a precipitatingevent.

Clinical pattern: acute renal failure

Type 2 HRS: is characterized by moderate renal failure (serumcreatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with asteady or slowly progressive course.

Clinical pattern: refractory ascites


HRS-AKI

2019


UIMH

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.

2019


UIMH

Rate of response in patients with type 1 HRS according to the schedule of i.v. administration of terlipressin

55,88

45,95

20,59 18,9

0

20

40

60

80

100


Complete response Partial response

% P = N.S.

M. Cavallin et. al. 2016 ; 63 : 983-992

2019


UIMH

42

2,23

3,51

0

2

4

6


mg

/24

hr

Mean effective daily dose of terlipressin (mg/24 hours) accordingto its schedule of i.v. administration

M. Cavallin et. al. Hepatology 2016 ; 63 : 983-992.

P < 0.0001

2019


UIMH

Type I.V. Continuous infusion

(n° = 34)

I.V. Boluses

(n° = 37)

P

Total: pts (%) 7 (20.58 %) 16 (43.24 %) < 0.05

Suspected intestinal ischemia : pts

- 3 --

Peripheral ischemia: pts 1 - --

Circulatory overload: pts 2 5 --

Angina pectoris: pts 3 3 --

Arrhythmia: pts - 1 --

Arterial hypertension: pts 1 - --

Persistent diarrhea: pts - 2 --

Others: pts - 2 --

Severe treatment-related adverse events (defined as need to withdraw terlipressin) according to the schedule of i.v. administration of terlipressin

M. Cavallin et. al. Hepatology 2016 ; 63 : 983-992

2019


UIMH

TD. Boyer et al. Liver Transpl. 2011 ; 17 : 1328-1332

Survival in patients according to the treatment of type 1 HRS

%LT

Responders to terlipressin and albumin

Non responders to terlipressin and albumin

2019


UIMH

• Patients with advanced liver disease frequently show an acute impairmentof renal function (AKI).

• The KDIGO criteria should be applied for the diagnosis of AKI.• A new algorithm has been developed for a more rationale application of

the therapeutic resources (avoiding of potentially dangerous consequencesof an overtreatment of AKI as a consequence of an uncritical application ofthe KDIGO criteria)

• The definitive removal of the cut off of serum creatinine from the criteriafor diagnosis and treatment of HRS in the setting of AKI (HRS-AKI).

• The differential diagnosis between HRS-AKI and ATN-AKI is complex.• New biomarkers of glomerular filtration rate and parenchymal kidney

damage are promising tools in refining the evaluation of renal function inthese patients.

• Terlipressin plus albumin is an effective treatment for HRS-AKI.• RRT should be used in nonresponders when indicated.

Summary

S. Piano et al. Liver Int. 2017 ; 37 (Suppl 1) : 116-122

2019


UIMH

ml/

min

P < 0.01

P. Angeli et al. Hepatology 1999 ; 29 : 1690-1697.

Improvement of glomerular filtration rate in patients with HRS and complete response to treatment with vasconscrictors and albumin

2019


UIMH

M. Hultström et al. Physical. Genomics 2018 ; 50 ; 127-141.

The hierachical network of 114 connected genes in common in 6 different models of AKI

MyC

2019


UIMH

2019


UIMH

Temporal relationships between AKI, AKD and CKD in patients with cirrhosis

M. Tonon et al. 2019 ; EASL ILC 2019)


Definition Functional criteria Structural criteria

AKI Increase in sCr by 50%within 7 days or increasein sCr by 0.3 mg/dl within 2 days

No criteria

AKD

AKI or GFR < 60 ml/minper 1.73 m2 for < 3 months Kidney damage for < 3

monthsDecrease in GFR ≥ 35% or increase in sCr ≥ 50 % for < 3 months

CKD GFR < 60 ml/min per 1.73 m2 for > 3 months

Kidney damage for ≥ 3 months

Definition of Kidney Disease

2019


UIMH

National Kidney Foundation Kidney Disease Outcome Quality Initiative: Classification of CKD

With kidney damage Without kidney damage

GFR (ml/min/1.73m2) Stage Stage

>/= 90 1 Normal

60-89 2 Decreased GFR*

30-59 3 3

15-29 4 4

< 15 5 5

* may be normal for age

Kidney failure is defined as either a) GFR < 15 (ml/min/1.73m2), or b) a need to start renal replacement therapy (RRT)

AS Levey et al. Ann. Intern. Med. 2003 ; 139 : 137-147.

2019


UIMH

0 20 40 60 80 100 120

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

mGFR

CKD-EPI

MDRD4

MDRD7

Estimated Glomerular Filtration Rate (GFR) by serum creatinine-basedequations versus measured GFR

S. Rosi et al. Liver Int. 2015 ; 35 : 2108-2014

2019


UIMH


Definition Functional criteria Structural criteria

AKI Increase in sCr by 50%within 7 days or increasein sCr by 0.3 mg/dl within 2 days

No criteria

AKD

AKI or GFR < 60 ml/minper 1.73 m2 for < 3 months Kidney damage for < 3

monthsDecrease in GFR ≥ 35% or increase in sCr ≥ 50 % for < 3 months

CKD GFR < 60 ml/min per 1.73 m2 for > 3 months

Kidney damage for ≥ 3 months

Definition of Kidney Disease

2019


UIMH

M. Tonon et al. 2019 ; EASL ILC 2019)

0,00

0,20

0,40

0,60

0,80

0 12 24 36 48 60

AKD

No AKD

Five-year probability of survival according to the diagnosis of AKD in patients with cirrhosis

%

< p < 0.01

2019


UIMH

Clinical types of HRS

Type 1 HRS : rapidly progressive reduction of renal function asdefined 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 mayoccurs spontaneously, but it can also follow a precipitatingevent.

Clinical pattern: acute renal failure

Type 2 HRS: is characterized by moderate renal failure (serumcreatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with asteady or slowly progressive course.

Clinical pattern: refractory ascites


HRS-AKI

2019


UIMH

Proposal of a new classification of hepatorenal syndrome

P. Angeli et al 2019 (manuscript submitted)

Old classification New classification Criteria

Type 1 HRS HRS-AKI a) Absolute increase in sCr ≥ 0.3 mg/dl within 48 hours

and/or

b) Urinary output ≤ 0.5ml/Kg B.W. ≥ 6 hours*

or

b) Percent increase in sCr ≥ 50 % using the last availablevalue of outpatient sCr within 3 months as the baselinevalue

Type 2 HRS HRS-NAKI HRS without the criteria for AKI

• HRS-AKD Decrease in GFR ≥ 35% or eGFR <60 mL/min per 1.73 m2

for < 3 months in the absence of other (structural) causes

• HRS-CKD eGFR < 60 mL/min per 1.73 m2 for 3 months in the absence of other (structural) causes

2019


UIMH

Potential indications and timing for RRT in patients with cirrhosis

CKD (stage 4-5)Kidney failure

AKI-ATN(stage 2 or 3)

AKI-HRS(stage 2 or 3) with no response to terlipressin

plus albumin

• Refractory fluid overload

• Severe eletrolyte imbalance

• Severe acid-base imbalance

• Symptomatic azotemia

• Refractory hepatic encephalopathy

Indications Timing

Persistent AKI

2019


UIMH

80

100

120

140

160

180

200

0 1 24

Changes in arterial ammonia concentration after CVVH in patients with cirrhosis

AJ. Slak, et al. Liver Int. 2014 ; 34 : 42-48

hr

μm

ol/

l

2019


UIMH

Probability of ICU Mortality in patients with cirrhosis and AKI before or after RRT according to number of organ failure/s

K. Staufer et al. Liver Int. 2017 ; 37 : 843-850

Number of organ failure (EASL-Clif)

1-2 3-4 5-6

On admission (n=78)

45.5% 75.6% 100%

24 hours prior RRT (n=66)

41.8% 71% 100%

24 hours after start of RRT (n=58)

38.5% 63% 100%

48 hours after start of RRT (n=39)

22.2% 65% 100%

2019


UIMH

Presentazione di PowerPoint · Hepatorenal syndrome P. Angeli, Dept. of Medicine, Unit of Internal...

Documents

Transcript of Presentazione di PowerPoint · Hepatorenal syndrome P. Angeli, Dept. of Medicine, Unit of Internal...