RENAL DISEASE IN END STAGE LIVER DISEASE

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RENAL DISEASE IN END STAGE LIVER DISEASE

Mitchell L Shiffman, MD Director

Liver Institute of Virginia Bon Secours Health System

Richmond and Newport News, VA

Bon Secours Liver Institute of Virginia

Mitchell L Shiffman, MD POTENTIAL CONFLICTS OF INTEREST

Company Roles Abbvie Advisor meetings, Grant support, Speaker Bayer Speaker Bristol Myers-Squibb Advisor meetings, grant support, Speaker Conatus Grant support CymaBay Grant support Daiichi Sankyo Speaker Exalenz Grant support Galectin Grant support Genfit Grant support Gilead Advisor meetings, Grant support, Speaker Intercept Advisor meetings, Grant support, Speaker, Immuron Grant support Merck Grant support, Advisor meetings, Speaker, NGMBio Grant support Novartis Grant support Optum Rx Consulting Salix Advisor meeting Shire Grant support

Copyright © 2015 The Royal College of Physicians and Surgeons of Canada. http://rcpsc.medical.org/canmeds. Reproduced with permission.”3

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RENAL DISEASE IN ESLD CATEGORIES

• Renal disease develops in 20-25% of patients with cirrhosis Systemic disorder causing renal and liver disease A renal disease which is separate from the liver disease Renal disease that is caused by ESLD

• Overall survival is poor: 50% at 1 month 20% at 6 months

TA Gonwa, HM Wadei. Am J Kidney Dis 2013;62:1198–212. P Gines, RW Schrier. N Engl J Med 2009;361:1279–90.


RENAL DISEASE IN ESLD CASE 1-SYSTEMIC DISORDER

66 year old male with chronic HCV and bridging fibrosis by LBX. He had a virologic response then relapse with PEGINF and RBV in 2010 and PEGINF-BOC-RBV in 2012. He now has increasing lethargy, swelling of the abdomen and lower extremities. EXAM: Sclera anicteric, obvious ascites, 3+ lower extremity edema. LABS: Sodium 141, creatinine 3.1 mg/dL, TBILI 1.0 mg/dL, albumin 1.5 g/dL, INR 1.0 UA: 4+ protein, 1+ blood CTP 8, MELD 20, US: Echogenic liver consistent with chronic liver disease. No liver mass. Normal PV blood flow. Mild ascites.


RENAL DISEASE IN ESLD SYSTEMIC DISORDERS

Liver Disease Renal Disease Viruses Chronic HCV or HBV Glomerulonephritis Metabolic syndrome NASH Diabetic nephropathy Infiltrative disorders Amyloidosis

Myeloma Amylodosis Myeloma

Hypotension Shock liver ATN Drug toxicity Acute necrosis ATN


RENAL DISEASE IN ESLD CASE 2-UNRELATED DISEASES

A 42 year old female with cirrhosis secondary to ETOH. She has never developed a complication of cirrhosis. She has not consumed ETOH since she first found out she had cirrhosis. PMH is significant for poorly controlled HTN and CKD with baseline Screat 3.5 mg/dL. EXAM: No ascites. No edema. No asterixis. LABS: Sodium 141, creatinine 3.8 mg/dL, TBILI 1.0 mg/dL, albumin 4.0 g/dL, INR 1.0 CTP score 7, MELD 19, Fibroscan 42 kPa US: Echogenic liver consistent with cirrhosis. No liver mass. Normal

PV blood flow. Mild ascites.


RENAL DISEASE IN ESLD BASIC PRINCIPLES

• The kidney is more susceptible to acute injury in patients with cirrhosis Dehydration Hypotension Medications

• Serum creatinine under estimates GFR in patients with cirrhosis Especially in patients with muscle wasting Screat of > 1.5 mg/dL is indicative of severe renal impairment

• Ascites precedes the development of CKD or HRS in patients with cirrhosis

• Kidney function declines with worsening liver disease and leads to excess mortality

NK Bozanich, PY Kwo Clin Liver Dis 2015: 19; 45-56.


RENAL DISEASE IN ESLD IMPACT ON MELD SCORE

10

15

20

25

30

35

1.0 1.5 2.0 2.5 3.0 3.5 4.0

MEL

D S

CO

RE

Serum Creatinine (mg/dL)

140135130125

• For patients with moderate liver impairment: TBILI of 2.5 mg/dL INR 1.5

• Screatinine has the greatest impact on MELD score

• In general there is a 1 point increase in MELD for each 0.25 point increase in Screat

• Hyponatremia increases the MELD especially when this is low

Sodium


RENAL DISEASE IN ESLD CASE 3-DRUG TOXICITY A 67 year old male with cirrhosis secondary to Primary HFE. A variceal bleeding 1 year ago was treated with banding. Mild ascites resolved with step 1 diuretics. Mild HE is well controlled with lactulose QD. Phlebotomy has reduced ferritin to under 50 ng/ml. He developed severe hip pain has been taking NSAIDS for the past 3 months. EXAM: No obvious ascites. 2+ lower extremity edema. LABS: Sodium 141, creatinine 2.4 mg/dL, TBILI 1.5 mg/dL, albumin 3.5 g/dL, INR 1.3 CTP 8, MELD 19 Urine NA 45 mEq US: Echogenic liver consistent with cirrhosis. No liver mass. Normal PV

blood flow. Mild ascites.


AKI AND CIRRHOSIS AVOID NEPHROTOXIC AGENTS

• Cirrhosis increases the susceptibility of the kidney to develop acute nephrotoxicity

• NSAIDs Inhibit renal prostaglandin production Decrease GFR

• Neomycin Portal hypertension increases intestinal mucosal permeability

• ACE inhibitors Lead to sodium retention

• IV contrast during imaging studies


NSAID INDUCED AKI WITH CIRRHOSIS PROGNOSIS

0

1

2

3

4

5

0 4 8 12 16 20

Seru

m C

reat

inin

e (m

g)

DAYS

Persistent

Transient

0

20

40

60

80

100

0 15 30 45 60 75 90

SUR

VIVA

L %

DAYS

C Eliara et al. J Hepatol 2015; 63:593-60.


CIRRHOSIS AND PORTAL HYPERTENSION IMPACT ON RENAL FUNCTION

Portal Hypertension

Decrease SVR

Increased Cardiac Output

Increase Renin-Angiotensin

Increase Vasopressin

Sodium retention

Increased epinephrine Sympathetic tone

Bacterial translocation

Inflammatory cytokines

Dilatation of splanchnic arteries

Decreased GFR

Water retention


RENAL DISEASE IN ESLD ROLE OF ASCITES

0

20

40

60

80

100

0 2 4 6 8 10

% o

f Pat

ient

s

YEARS G D’Amico et al. J Hepatol 2006; 44:217-231.

• The MOST common complication of ESLD

• Leads to other complications: SBP Hyponatremia AKI CKD Hepatorenal syndrome


COMPLICATIONS OF ASCITES INCREASE MORTALITY

020406080

100

0 20 40 60 80 100

SUR

VIVA

L (%

)

MONTHS

NoneSBPRefractoryHypo-NaHRS

R Planas et al. Clin Gastroenerol Hepatol 2006; 1385-1394.


RENAL DISEASE IN ESLD CASE 4-ACUTE AKI

• Most patients with cirrhosis and AKI do not have HRS

• Dehydration from Diuretics Bleeding

• Readily reversible: Volume expansion IV albumin to limit ascites Some normal saline Stop diuretics

0

1

2

3

4

5

0 4 8 12 16 20

Scre

atin

ine

(mg/

dL)

DAYS

IV albumin 25 gm Q6H


RENAL DISEASE IN ESLD CASE 5–HYPONATREMIA

45 year female with cirrhosis secondary to NASH. She developed ascites for the first time 1 year ago. This initially resolved with step 1 diuretics. This is her 6th hospitalization in the past 3 months for ascites and AKI. During each hospitalization she is given 0.9% NS to correct hyponatremia and started back on diuretics. She has had 6 paracentesis removing 5-8 liters each. HE is treated with lactulose and rifaxamine. EXAM: 5’2”; 250 pounds, distended abdomen with obvious ascites, 4+

edema to the hips. Mild HE. No muscle wasting. LABS: Sodium 115, K 4.5, creatinine 2.1 mg/dL, TBILI 1.1 mg/dL, Albumin 1.8 g/dL, INR 1.3, CTP 10, MELD 26


HYPONATREMIA AND AKI INTRAVENOUS ALBUMIN

0

1

2

3

4

5

90100110120130140150

0 2 4 6 8 10 12 14 16 18

CR

EATI

NIN

E (m

g/dl

)

SOD

IUM

(mEq

/L)

DAYS

SodiumCreatinine

PA McCormick et al. Gut 1990; 31:204-207.

IV Albumin 25 gm Q6H


RENAL DISEASE IN ESLD ROLE OF IV ALBUMIN

• Improves vascular oncotic pressure Enhances movement of tissue fluid into vasculature Decreases edema Decreases ascites

• Expands vascular space Improves renal perfusion Enhances urine output Increases serum sodium Lowers Serum Creatinine

• Dose is 25 gm Q 6 H until Anasarca resolved Sodium back to normal Creatinine back to normal or plateaued Start diuretics once Sna > 130


SEVERE ASCITES AND ANASARCA IV ALBUMIN

• Start IV albumin 25 gms • Q6 hours • Large volume paracentesis on

admission • Use for several days until serum

sodium improved and creatinine is normal then add diuretics

• Continue IV albumin until serum sodium is normal

• Discharge on oral diuretics • Anasarca

0

5

10

15

20

25

30

60

70

80

90

100

110

120

A P 1 2 3 4 5 6 7

Cum

ulat

ive

UO

(L)

Wei

ght (

kg)

DAYS

Albumin 25gmQ6H Diuretics


IV ALBUMIN IN SBP

• Occurs in 30% with ascites • In hospital mortality 20% • Mortality and AKI reduced

significantly with IV albumin RCT, N=126 Cefotaxime + IV albumin Mean age 60 years ETOH cirrhosis 30% Mean CTP score 10 Culture positive 54% E Coli 21%

0

10

20

30

40

50

AKI In-Hospital 3 month%

of P

atie

nts

Mortality

CTMCTM+ALB

P Sort et al N Engl J Med 1999; 341:403-409.


IV ALBUMIN AS MAINTENANCE THERAPY

ALB SOC p Survival 77% 66% 0.028

OR Paracentesis 0.46 Refractory ascites 0.54 SBP 0.32 Non-SBP infections 0.70 AKI 0.50 HRS 0.38 HE Stage III-IV 0.48 Variceal bleeding 1.07

• Randomized controlled trial • SOC vs IV albumin • 40 mg BIW x 2 weeks then QW • N=431 • 33 Italian centers • Inclusion criteria: Ascites Spironolactone >200 mg/d Furosemide > 25 mg QD

P Caraceni et al. EASL 2017


RENAL DISEASE IN ESLD HEPATORENAL SYNDROME

• Cirrhosis and ascites Serum creatinine > 1.5 mg/dL Urine sodium <10 mEq/L Urine output less than 500 cc/day Serum sodium < 130 mEq/L Absence of hematuria, proteinuria or intrinsic renal disease Absence of urinary tract obstruction No response to volume expansion with IV albumin

• Type 1: Cirrhosis with rapidly progressive renal failure • Type 2: Cirrhosis with subacute renal failure • HRS in the setting of ALF

F Salerno J Hepatol 2007; 47:729-731.


HEPATORENAL SYNDROME TYPE 1 AND TYPE 2

Type 1 Type 2 Rapid rise in Screat which doubles to >2.5 mg/dL within days - 2 weeks

Slow rise in Screat over weeks to months

Precipitating factor No precipitating factor Infection Bacterial infections

Fugal infections SIRS related to infections

Acute on chronic liver injury DILI including ETOH Acute hepatitis Shock liver

Renal hypoperfusion Sepsis with hypotension Variceal bleeding


HEPATORENAL SYNDROME RISK

0102030405060

10 18 ETOH ALF

RIS

K O

F H

RS

(%) 1 Year

5 Years

MELD Score Patients with Cx and Acites

Hepatitis DF>32

SJ Munoz Med Clin NA 2008; 92:813-837.


HEPATORENAL SYNDROME SURVIVAL

0

20

40

60

80

100

0 100 200 300 400 500 600

SUR

VIVA

L (%

)

DAYS

Type 1Type 2No HRS

V Arroyo et al. J Hepatol. 2007; 935-946.


TREATMENT OF HRS MIDODRINE+OCTREOTIDE

0

50

100

0 4 8 12 0 4 8 12

C Skagen et al. J Clin Gastroenterol 2009; 43:680-685.

SUR

VIVA

L (%

)

WEEKS WEEKS

-505

1015202530

HRS1 HRS2

Cha

nge

in C

rCl M+OCT+ALB

Control

HRS Type 1 N=102

HRS Type 2 N=60


TREATEMENT OF HRS TERLIPRESSIN

0

50

100

0 4 8 12 0 4 8 12

M Cavallin et al. Hepatology 2015; 62:567-574.

SUR

VIVA

L (%

)

WEEKS WEEKS

020406080

100

TERLI M+OCT

Res

pons

e (%

) PartialComplete

Terlipressin+ALB N=27

M+OCT+ALB N=22


PORTAL HYPERTENSION BETA-BLOCKERS

• A primary treatment for patients with portal hypertension • Reduces risk of first variceal bleeding • Reduces risk of rebleeding from esophageal varices • Reduces bleeding in severe portal gastropathy • This does not mean that all patients with cirrhosis should be taking

beta-blockers Effective in patients with larger varices Does not prevent varices from appearing or growing Beta-blockers have adverse events May lead to AKI and increase mortality in patients with ascites


BETA-BLOCKERS IMPACT OF ASCITES

0

20

40

60

80

100

0 6 12 18 24 30 36

SUR

VIVA

L (%

)

MONTHS

NoYes

T Serste et al. Hepatology 2010; 52:1017-22.

Beta-Blockers


BETA-BLOCKERS IMPACT OF SBP

Use of beta-blockers significantly increased the risk of AKI and HRS in patients who developed SBP RCT, N=602 Mean age 57 years ETOH cirrhosis 55% Mean MELD 17 Child class C 50% 90 day mortality with AKI in

patients on beta-blockers and h/o SBP is 80%

0

10

20

30

40

50

AKI HRS%

of P

atie

nts

BBNo BB

M Mandorfer et al Gastroenterol 2014; 146:1680-1690.


RENAL DISEASE IN ESRD SUMMARY

• Not all renal dysfunction in cirrhosis is HRS • Avoid nephrotoxic agents in patients with cirrhosis • IV albumin is essential for treating the complications of renal

disease in ESLD Hyponatremia AKI Anasarca SBP to reduce risk of HRS Adjunct to treatment of HRS

• Propranolol should not be used in patients with ascites

RENAL DISEASE IN END STAGE LIVER DISEASE

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