renal injury in cld

1. ACUTE KIDNEY INJURY
IN LIVER DISEASE

2. CONTENTS
• DEFINITION
• TYPES
• PATHOPHYSIOLOGY
• DIAGNOSIS
• TREATMENT
• PREVENTION

3. DEFINITION
Acute Kidney Injury(ICA 2015)
• ≥0.3mg/dl increase in sCr in last 48 hr
• ≥50% increase in sCr in last 7 days
• Urine output < 0.5ml/kg/hr ≥ 6hr
Hepatorenal syndrome(ICA 2007)
• Cirrhosis with ascites
• sCr≥1.5mg/dl(133µmol/L)
• No or insufficient improvement,48 hr after diuretic withdrawl & albumin infusion
• Absence of shock/intrinsic renal disease
• No evidence of recent use of neprotoxic agent
Angeli P. J Hepatol (2015)

4. TYPES
1.Pre renal
2.Intrinsic
3.Post renal
4.HRS
Charlton MR et al. Liver Transpl 2009;15:S1

5. EPIDEMIOLOGY
• AKI 15%-25%(hospitalized cirrhotic patients)
Prevalance of HRS
Cirrhotic/SBP/infections30%
Severe Alcoholic Hepatitis25%
Serial LVP10%
10-30% HRS
G low et al Gasteroenterol Res Pract 2015

6. PATHOPHYSIOLOGY

7. SPLANCHNIC VASODILATION THEORY
G low et al Gasteroenterol Res Pract 2015

8. SYSTEMIC INFLAMMATION(ACLF)
Endotoxin
bacterial DNA
Monocyte
TNF @
IL6
IL1B
TLR4
Apoptosis
Tubular
damage
Trebicka J et al Front Immunology 2019

9. HRS PATHOGENESIS
COMPLEX
Ficket P et al Hepatology 2013
Angeli P et al J Hepat 2019
Bile salt mediated

10. HRS MEDIATORS
Pathology Mediators
Splanchnic Vasodilation NO, CO, & endogenous cannabinoids
Bacterial translocation
Pro-inflammatory cytokines
Peripheral & renal vasoconstriction
Sodium & water retention
Renin–angiotensin system(RAAS)
Sympathetic nervous system activation
Arginine vasopressin hypersecretion(AVP)
Precipitating/triggering events Hypovolemia (excessive diuretic use,
diarrhea), GI bleed, SBP, LVP without
plasma expansion
Gines P et al. N Engl J Med 2009;361:1279
Wiest R et al. Hepatology 2005;41:422

11. DIAGNOSIS

12. Diagnostic criteria of HRS
ICA criteria(2007)
• HRS type 1
• Rapid progressive renal failure
• doubling of the initial S Cr to level > 2.5 mg/dl in < 2 week
• 50% reduction of initial 24 hr CrCl < 20ml/min in < 2 week
• Often develops after a precipitating event
• Median survival 1-2 weeks
• HRS type 2
• Moderate renal impairment with steady progressive course
• evolving over weeks to months
• sCr between 1.5 to 2.5 mg/dl
• Develops de novo in patients with refractory ascites
• Median survival around 6 months
Paulo Angeli et al. Hepatology 2019;23:164
ICA Criteria 1996
Major
1. CLD/ALD with PHT
2. Creat>1.5mg/dl or CrCl<40ml/min
3. Absence of shock/infection/fluid
loss/nephrotoxic drug
4. No improvement after withdrawl
of diuretic and volume expansion
with 1.5l saline
5. Proteinuria<500mg/d
6. No obstruction/parenchymal
disease
Minor
1. Urine output<500ml/day
2. Urine sodium<10meq/day
3. Urine osmolality>plasma
osmolality
4. Urine RBC<50/hpf
5. Ser sodium<130meq

13. FALLACIES:FIXED CREATININE VALUE
• In patients with cirrhosis, sCr is also affected by:
Decreased formation of creatinine from creatine in muscles, secondary to
muscle wasting
Increased renal tubular secretion of creatinine
Increased volume of distribution in cirrhosis may dilute sCr
Interference with assays for sCr by elevated bilirubin
• Under diagnosis of AKI/HRS (overestimation of GFR)
• Fixed threshold does not take into account the dynamic changes in serum
Cr that occur in the preceding days or weeks
• Severity of AKI/HRS could not be assessed

14. International Club of Ascites (ICA-AKI)
AKI in cirrhosis (2015)
Angeli P. J Hepatol (2015)
Stage 1A: sCr<1.5mg/dl
Stage 1B: sCr≥1.5mg/dl

15. Newly added diagnostic criteria for HRS-AKI

16. HRS SUBTYPES
Angeli P et al, journal of hepatology 2019. vol 71

18. Differentiating the pre renal AKI
from acute tubular necrosis (ATN)
Charlton MR et al. Liver Transpl 2009;15:S1

19. Role of urinary biomarkers in AKI
differential diagnosis
Fagundes C et al. J. Hepatol. 2012 ; 57 : 267–273
Belcher J M et al. Hepatol. 2014;60:622
Huelin P et al J Hepatology 2019
220µg/g Cr

20. TREATMENT

21. TREATMENT
• Vasoconstrictor Therapy
• TIPS
• Extracorporeal Support Systems
• Liver Transplantation

22. TRIALS RELATED TO
TERLIPRESSIN

23. Terlipressin
• Triglycyl-lysyl Vasopressin
• 0.5–1 mg every 4–6 hr intravenously.
• Increase up to 2 mg every 4–6 hr until serum creatinine
decreases to 1–1.2 mg/dl
• Usual duration of therapy, 5 to 15 days.
• Continuous administration as effective as I.V. bolus dose
Lower dose/lower rate of adverse effect
Moreau et al.,Fabrizi et al., Gluud et al., Sanyal et al., and Martín-Llahí et al.

24. 1.Terlipressin in HRS
• Multicenter double blinded RCT
• Acute/chronic Liver disease with
HRS type 1 diagnosed by
ICA criteria
• Treatment discontinued if
• Treatment failure
• Liver transplantation
• Adverse effects
• If treatment success achieved,
discontinue or continue drug at
investigator discretion till
max. of 14 days
Placebo
Albumin 25g/d
N =56
180 d
0 14 d
3 d
Terlipressin 1mg q6h
Albumin 25g/d
N =56
Dose increased to 2mg q6h
if Cr decrease <30%
Albumin 100g on day 1
Sanyal A J et al. Gastroenterology 2008; 134(5): 1360

25. Terlipressin in HRS
Study end points definition
Treatment success
(primary end point)
At day 14, Cr ≤ 1.5 mg/dl on 2 occasions 48h apart
No dialysis
No death
No recurrence of HRS before day 14
HRS reversal Cr ≤ 1.5 mg/dl during treatment
No dialysis
Partial response Cr decrease by 50% from baseline but >1.5 mg/dl
No dialysis
No recurrence of HRS
Treatment failure At day 14, Cr ≥ baseline after 7 days
Dialysis
Death
Sanyal A J et al. Gastroenterology 2008; 134(5): 1360

26. Terlipressin in HRS
Response
Terlipressin
n=56
Placebo
n=56
P value
Median treatment
duration
6.3 d 5.8 d
Treatment success 14 (25%) 7 (12.5%) 0.093
HRS reversal 19 (34%) 7 (12.5%) 0.008
Partial response &
treatment success
16 (29%) 10 (18%) 0.181
Treatment failure 31 (55%) 37 (56%) 0.247
Ser Creatinine improved (-0.7mg/dl) vs (0.0mg/dl) with p<0.009
One patient in each group had recurrence of HRS that reversed after retreatment
HRS reversal maintained in 19 at 30 days & in 12 at 60 days of follow up/placebo(4D)
Sanyal A J et al. Gastroenterology 2008; 134(5): 1360

27. Terlipressin in HRS
Survival benefit
No difference in survival at
180d
HRS reversal maintained at 180 d
Survival better
Sanyal A J et al. Gastroenterology 2008; 134(5): 1360

28. Predictors of response (HRS reversal) to
terlipressin
Sanyal A J et al. Gastroenterology 2008; 134(5): 1360
T.D. Boyer et al. J. Hepatol. 2011 ; 55 ; 315
One non fatal myocardial infarction with terlipressin
Overall adverse events rate was similar to placebo
Terlipressin requires 3 days to show benefit

29. 2.Terlipressin in HRS
• Pooled patient-level data(308 patients/HRS type 1)
• Two large phase 3, multicenter, placebo-controlled RCTs
• OT-0401 (112 pt) and REVERSE (196 pt)
Analysis
HRS reversal [SCr≤133 µmol/L] (primary end point)
90-day survival
need for renal replacement therapy
predictors of HRS reversal
A J Sanyal et al Alimentary pharmacology 2017

30. Terlipressin in HRS
HRS Reversal
P=0.008
P=0.004
A J Sanyal et al Alimentary pharmacology 2017

31. Terlipressin in HRS
Change in Baseline Ser Creatinine
A J Sanyal et al Alimentary pharmacology 2017

32. Terlipressin in HRS
Survival Benefit
A J Sanyal et al Alimentary pharmacology 2017
P=0.7162 P=0.5588
p<0.0001
P=0.0026
P<0.0001
P=0.036

33. Terlipressin in HRS
Predictors of Survival
• Lower MELD score
• Lower Ser Creatinine
• Lower total bilirubin
• Absence of alcoholic hepatitis
• Lower MAP
• Absence of precipitating factors for HRS at baseline
• Male sex

34. TERLIPRESSIN
• HRS reversal(30-40%)
• Survival: short term benefit may be/no difference in long term survival
Trials with more number of patients may reveal the actual figure
Limited by severity of disease
Terlipressin not acting on the basic underlying liver disease
Fixed Cr definition leading to late diagnosis
• Survival is definitely better in pt who achieve HRS reversal irrespective of
treatment received
• 3 days for terlipressin to show effect
• Pt who underwent transplant with lower ser creatinine value had better
post transplant outcome

35. TERLIPRESSIN
VS
NORADRENALINE

36. NORADRENALINE
• Alpha adrenergic agonist
• 0.5–3 mg/hr given as continuous intravenous infusion
• Inexpensive/readily available
• Aim of increasing mean arterial pressure by 10 mm Hg
• Treatment is maintained until serum creatinine decreases to 1–1.2 mg/dl

37. 1.Terlipressin Vs Noradrenaline in HRS
N =23
30 d
0 15 d
3 d
Terlipressin 0.5mg q6h
Albumin 20g/d adj. to CVP
N =23
Dose increased to 2mg q6h
if Cr decrease < 1mg/dl
Singh V et al . J Hepatol 2012;56:1293
Norad 0.5mg/h increased upto
3mg/h till MAP increase by
10mmHg or 4hr UO>200ml
Albumin 20g/d adj. to CVP
• Randomized/Non blinded
• Cirrhosis/ascites/HRS type 1
diagnosed by ICA criteria (2007)
• Reversal of HRS =
reduction of Cr to <1.5 mg/dl
• Survival assessed at day 15 & 30

38. 1.Terlipressin Vs Noradrenaline in HRS
Terlipressin
n=23
Noradrenaline
n=23
P
value
Mean treatment duration 7.82 ± 3.12 d 9.3 ± 4.0 d
HRS reversal 9 (39%) 10 (43%) 0.764
Survival at Day 15 9 (39%) 11 (48%) 0.461
Singh V et al . J Hepatol 2012;56:1293
Cost effective
975€(Terli) vs 275€(Noradr)
Baseline CTP predictive of
response

39. 2.Terlipressin Vs Noradrenaline in HRS
Ghosh S et al. Liver Int. 2013: 33: 1187
N =23
90 d
0 15 d
3 d
Terlipressin 0.5mg q6h
Albumin 20g/d adj. to CVP
N =23
Dose increased to 2mg q6h
if Cr decrease < 1mg/dl
Norad 0.5mg/h increased upto
3mg/h till MAP increase of
10mmHg
Albumin 20g/d adj. to CVP
• Randomized Pilot study
• Non blinded
• HRS type 2 diagnosed by
ICA criteria (2007)
• All patients had creatinine
between 1.5 to 2.5 mg/dl
• Reversal of HRS =
reduction of Cr to <1.5 mg/dl
Terlipressin
n=23
Noradrenaline
n=23
P
value
Mean treatment duration 8.6 ± 3.2 d 8.7 ± 3.8 d
HRS reversal 17 (74%) 17 (74%) 1.0
Survival at Day 90 15 (65%) 14 (61%) 0.461
804 vs 311 USD

40. META-ANALYSIS
Arjun Nanda et al J clin gastroenterol 2018
Terli vs placebo
Terli vs Noradr
• Noradr is as effective as terlipressin
• Studies are small/underpowered/unblinded
• No survival benefit
• Cost effective

41. MIDODRINE

42. MIDODRINE
• Alpha agonist
• 7.5 mg TDS , increase upto 12.5 mg TDS if needed
• Titrate to an MAP increase of at least 15 mm Hg
• Used in association with octreotide (100 μg SC TDS, increase upto 200 μg TDS)
Angeli et al. and Wong et al

43. Midodrine and Octreotide vs Dopamine
Angeli P et al Hepatology 1999
2 liver transplantation/2 died(76day/29day)/ 1 alive at 472 day
5 patients 8 patients
3/5 discharged after 20 days 7/8 died within 12 days
13 HRS1 patients
Midodrine+octreotide+albumin Dopamine(non pressor dosages)+albumin
dopamine midodrine
Survival 30D
Midodrine + octreotide
dopamine

44. Midodrine & Octreotide in HRS
• Retrospective study of 60 patients with type 1 HRS treated with
midodrine/octreotide compared with 21 untreated controls
• Dose of drugs titrated to achieve MAP increase of 15 mmHg
• Octreotide 100 to 200 µg TID subcutaneous
• Midodrine 5, 7.5, 10, 12.5 & 15 mg TID oral
• Outcome measured - HRS reversal & survival at 30 days
Treatment group
n=60
Control group
n=21
P value
Sustained reduction of Cr 24 (40%) 2 (10%) 0.01
Death at 30 days 26 (43%) 15 (71%) 0.03
Esrailian E et al. Dig Dis Sci (2007) 52:742

45. TERLIPRESSIN Vs MIDODRINE
• RCT(ITALY)
• 49 patient/Both HRS1 and HRS2
• 27 terlipressin+albumin
• 22 midodrine+octreotide+albumin
Cavallin et al J hepatology 2016
Terlipressin+albumin Midodrine+Oct+Albumin
Complete response(Cr<1.5) 15/27(55.5%) 1/21(4.8%)
Survival at 3 month
(no rescue tx)
14/21(67%) 9/21(43%)
P<0.01
P<0.001

46. MIDODRINE + OCTREOTIDE
• Midodrine with octreotide can be used as an alternative in cases
where terlipressin and Noradrenaline not available
• Efficacy and survival far lower compared to terlipressin
• Larger RCTs needed to establish exact effectiveness
• No major adverse effect compared to terlipressin in multiple small
studies

47. TIPS

48. TIPS in HRS
• Median interval between first detection of renal failure to TIPS
• Type 1 HRS 2.2 (0.3-6) weeks
• Type 2 HRS 4 (1.5-5) weeks
• Type 1 HRS patients had more advanced degree of liver dysfunction, higher Cr &
lower GFR
• Post TIPS
• Ascites improved in 14 & completely resolved in 10
• Encephalopathy worsened in 8 & occurred de novo in 3
41 non transplant candidates with HRS
10 excluded
Bili >15, CTP >12, severe encephalopathy
14 of HRS type 1 underwent TIPS
31 eligible candidates for TIPS
17 of HRS type 2 underwent TIPS
Brensing K A et al. Gut 2000;47:288

49. Post TIPS Response
Brensing K A et al. Gut 2000;47:288
creatinine Creatinine
clearance
7/31 (23%)
Non responder
1 died
*Renal function
worsened in all
Non TIPS pt
survival 3M 12M
TIPS 81% 48%
No TIPS 10%

50. TIPS in Refractory Ascites & HRS
type 2
• 70 patients with refractory ascites (excluding Type 1 HRS) randomized to either
TIPS (35) or LVP + albumin (35)
Primary end point: survival without LT
Secondary end point: recurrence of ascites or cost
Survival probability among
HRS type 2 patients
Probability of development of
de novo HRS or progression from
type 2 to type 1 HRS
Gines P et al. Gastroenterology 2002;123:1839
No survival benefit
Increase cost
Increase risk of HE
Low risk
Ascites recurrence
and HRS
progression
survival 1y 2y
TIPS 41% 26%
LVP 35% 30%

51. Summary
• Considering the short term effect of vasoactive drugs, TIPS may help to increase
survival in selected transplant ineligible candidates where it improves renal
parameters
• In refractory ascites and HRS2, TIPS may prevent the recurrence of ascites as well
as progression of HRS
• EASL guideline 2018: TIPS is contraindicated in HRS-AKI(severe liver dysfunction)
• Better larger RCTs needed to recommend its use currently in HRS

52. EXTRACORPOREAL
SUPPORT SYSTEM

53. MARS
(Molecular Adsorbent Recirculating System)
• Randomized multicenter study
• 13 HRS type 1 patients (CTP C/↑Bil)
• MARS+HDF 8 patients
• HDF 5 patients
• Primary end point 30D survival
• MARS treatment
• 6 to 8h session/day
• Max 10 sessions
• Stopped if bilirubin elevation
<1mg/dl between sessions
• Control: Mortality 100%(D7)
• MARS: Mortality 62.5%(D7)
75%(D30)
Mitzner S R et al. LiverTransplant 2000;6:277
P<0.01

54. MARS
RELIEF study
• 189 ACLF patients randomized to either MARS + SMT (95) or SMT alone (94)
• MARS therapy
• 8h per session
• Initial 1-4 sessions in first 4 days
• Later 3 sessions per week upto max of 10 sessions
• MARS stopped if Cr<1.5, HE gd <1, & stable bilirubin for 2 consecutive days
MARS+SMT
28 day survival probability
SMT alone
Benares R et al. Hepatology 2013;57:1153
Significant decrease in
Creatinine and Bilirubin
Improvement in HE

55. Prometheus
(Fractionated Plasma Separation and
Adsorption)
HELIOS study
• 145 ACLF patients randomized to FPSA (77) or
SMT (68)
• Treatment protocol
• Week 1 & 2 = 5 & 3 sessions
• Week 3 = add. 3 sessions if no improvement
Survival
(D90)
FPSA SMT p
value
MELD > 30 48% 9% 0.02
HRS type 1 42% 6% 0.04
Change in bil
from baseline
-8 ±11 -0±9 <0.001
Kribben A et al. Gastroenterology 2012;142:782
Promising in refractory cholestatic pruritus

56. LIVER
TRANSPLANTATION

57. Liver transplantation
• Retrospective analysis of 726 LT patients
• 71 patients fulfilled HRS criteria (ICA 1996) pre transplant
Survival at 1 y Survival at 3 y
With HRS 80.3% 76.6%
Without HRS 90.7% 85.3%
Improvement in renal
function over first month
Lee J P et al. Liver Transplant 2012;18:1237
None required
long term RRT

58. Liver transplantation
Predictors of survival
Lee J P et al. Liver Transplant 2012;18:1237

59. Combined liver-kidney transplantation
Charlton MR et al. Liver Transpl 2009;15:S1

60. LIVER TRANSPLANTATION
• Only modality to reverse both liver dysfunction and HRS
• Postoperative complications and in-hospital mortality are higher in
patients transplanted with HRS than without HRS
• The duration/degree/type (HRS or acute tubular necrosis) of renal
dysfunction preoperatively are independent predictors of survival

61. PREVENTION

62. Role of Antibiotic
Primary prophylaxis of SBP
• 68 patients with cirrhosis & ascites with the following
 Ascitic fluid protein <1.5 g/dl
 Creatinine >1.2 mg/dl, serum sodium <130 mEq/L
 CTP >9, bilirubin >3 mg/dl
Randomized to Norfloxacin (400mg OD)/Placebo for 1Y
Fernandez J et al. Gastroenterology 2007;133:818
Primary end point:3M/1Y survival
Secondary end point:1Y probability of SBP/HRS

63. • 126 patients with ascites & SBP randomized to cefotaxime alone or
cefotaxime + albumin (1.5 g/kg on day 1 & 1 g/kg on day 3)
Prevention of HRS
Role of albumin in SBP
Sort P et al. N Engl J Med 1999;5:403

64. SUMMARY
Algorithm for workup and
management of AKI

65. Claire Francoz et al Clin J Am Soc Nephrol 14, May, 2019

66. SUMMARY
• Pure Functional HRS is less common
• Haemodynamic derangements, systemic inflammation,
oxidative stress and bile salt-related tubular damage may
contribute significantly
• Vasoconstrictors & albumin effective in less than 50% of HRS
patients
• Response to vasoconstrictors decrease with increasing severity
of renal dysfunction
• TIPS/ECAD – not better than vasoconstrictors
• Liver transplantation is the only effective treatment currently
• Prevention of HRS possible in few cases

67. THANK YOU