Dr. Vijay Kher MD,DM,FAMS,FRCPE, FIMSA

• Kidney transplantation

• Prevention of progression of renal disease

• Multiple orations and awards National & International

• More than 170 publications & 9 books

Chairman, Medanta Kidney & Urology Institute

Medanta Hospital, Gurgaon

For Chairpersons

Hepato Renal

Syndrome

Dr. Vijay Kher Chairman Deptt. of Nephrology & Txp. Medicine Medanta Kidney & Urology Institute Medanta – The Medicity Gurgaon, Haryana, India

Renal Dysfunction in Cirrhosis

Renal dysfunction -common complication in cirrhosis

Spectrum of kidney disease in cirrhosis includes both acute and chronic conditions

AKI -19% of cirrhotic patients admitted to hospital

CKD -approximately 1% of all patients with cirrhosis

Cirrhotic patients with renal dysfunction have higher morbidity than those without renal dysfunction

Majority of cases with renal dysfunction in cirrhosis are functional in nature

Garcia-Tsao G et al. Acute kidney injury in cirrhosis. Hepatology 2008;48: 2064-77

Renal Dysfunction in Cirrhosis

A prospective study of 562 patients with cirrhosis & renal dysfunction in a single centre

Acute kidney injury associated with infection - 46 %

Pre-renal AKI - 32 %

Hepato renal syndrome - 13 %

Parenchymal renal disease - 9 %

(e.g glomerulonephritis)

Martin – Llahi M et al – Gastroenterology 2011:140:480

Current diagnostic criteria for acute kidney injury (AKI) in the general population & in patients with cirrhosis

RIFLE Criteria AKIN Criteria KDIGO Criteria Conventional for

diagnosis of AKI in

cirrhosis

Diagnostic

Criteria

Increase in SCr

to >1.5 times

baseline, within

7 days; or GFR

decrease

>25%; or urine

volume < 0.5 ml/kg/h for 6 h

Increase in sCr by

>0.3 mg/dl (26.5

µmol/L) within 48

hrs; or increase in

sCr >1.5 times

baseline within 48

hrs; or urine volume <0.5

ml/kg/h for 6 h

Increase in SCr by >0.3

mg/dl(26.5 µmol/L) within

48 h; or increase in SCr

to >1.5 times baseline,

which is known or

presumed to have

occurred within the prior 7 days; or urine volume

<0.5 ml/kg/h for 6 h

A percentage

increase in sCr of

50 % or more to a

final value of

SCr>1.5 mg/dl (133

µmol/L)

Staging Risk: Stage 1: Stage 1: Not provided

SCr increase

1.5-1.9 times

baseline; or

GFR decrease 25-50 %; or

urine output <

0.5 ml/kg/h for

12 h

sCr increase 1.5-

1.9 times baseline;

or sCr increase

>0.3 mg/dl (26.5 µmol/L(; or urine

output <0.5

ml/kg/h for 6 h

sCr increase 1.5 -1.9

times baseline; or Cr

increase >0.3 mg/dl

(26.5 µmol/L); or urine output <0.5 mg/kg/h for

6-12 h

Paolo A et al. Journal of Hepatology 2015 vol 62; 968-974

Current diagnostic criteria for acute kidney injury (AKI) in the general population & in patients with cirrhosis

RIFLE Criteria AKIN Criteria KDIGO Criteria Conventional for diagnosis of AJKI in cirrhosis

Staging Injury Stage 2: Stage 2:

SCr increase 2.0-2.9

times baseline; or

GFR decrease 50-75 %; or urine output

<0.5 ml/kg/h for 12 h

sCr increase 2.0-2.9

times baseline; or

urine output <0.5 ml/kg/h for 12 h

SCr increase 2.0-2.9

times baseline; or

urine output <0.5 ml/kg/h for > 12 h

Failure Stage 3: Stage 3:

SCr increase >3.0

times baseline; or

GFR decrease 50-75% or sCr increase

>4.0 mg/dl (353.6

µmol/L) with an acute

increase of at least

0.5 mg/dl (44

µmol/L); or urine

output <0.3ml/kg/h

for >24 h; or anuria

for >12 h

sCr increase 3.0

times baseline; or

sCr increase >4.0 mg/dl (353.2µmol/L)

with an acute

increase of at least

0.5 mg/dl (44

µmol/L); or urine

output <0.3 ml/kg/h

for >24 h; or anuria >

12 h

sCr increase 3.0

times baseline; or

sCr increase to >4.0 mg/dl (353.6 µmol/L);

or initiation of renal

replacement therapy;

or urine output <0.3

ml/kg/h for > 24h; or

anuria for >12 h

Paolo A et al. Journal of Hepatology 2015 vol 62; 968-974

International Club of Ascites (ICA-AKI) new definitions for the diagnosis & management of AKI in patients with cirrhosis

Subject Definition

Baseline sCr A value of sCr obtained in the previous 3 months, when available, can be used as baseline sCr. In patients with more than one value within the previous 3 months, the value closest to the admission time to the hospital should be used. In patients without a previous sCr value, the sCr on admission

should be used as baseline

Definition of AKI • Increase in sCr>0.3 mg/dl (>26.5 µmol/L) within 48 hrs; or • A percentage increase sCr >50 % from baseline which is known,

or presumed to have occurred within the prior 7 days

Staging of AKI • Stage 1: increase in sCr >0.3 mg/dl (26.5 µmol/L) or an increase in sCr >1.5 fold to 2-fold from baseline

• Stage 2: increase in sCr > 2 fold to 3 fold from baseline • Stage 3: increase of sCr> 3 fold from baseline or sCr >4.0 mg/dl

(353.6 µmol/L) with an acute increase > 0.3 mg/dl (26.5 µmol/L) or initiation of renal replacement therapy

Paolo A et al. Journal of Hepatology 2015 vol 62; 968-974

International Club of Ascites (ICA-AKI) new definitions for the diagnosis & management of AKI in patients with cirrhosis

Subject Definition

Progression of

AKI Progression Regression

Progression of AKI to a higher stage and / or need for RRT

Regression of AKI to a lower stage

Response to treatment

No response Partial response Full response

No regression of AKI Regression of AKI stage with a reduction of sCr to 0.3 mg/dl (26.5 µmol/L) above the baseline value

Return of sCr to value within 0.3 mg/dl (26.5 µmol/L) of the baseline value

Paolo A et al. Journal of Hepatology 2015 vol 62; 968-974

Causes of Acute kidney disease in Cirrhosis

Pre-renal (functional) failure

– Hypovolemia, GI Bleeding

– Drugs ( Aminoglycosides, non steroidal anti inflammatory drugs, diuretics)

Acute tubular necrosis

– Drugs (aminoglycosides, non steroidal anti-inflammatory drugs)

– Contrast agents

– Sepsis, Bleeding

Hepatorenal syndrome (type I)

Hepatorenal Syndrome (type II)

Interpretation of serum creatinine in Cirrhosis

Synthesized in liver, stored in muscles where it gets

phosphorylated to creatinine

Inaccurate marker of renal function, more so in cirrhotic patients

Influenced by - age, gender, ethnicity, muscle mass and daily

protein intake

In liver disease serum creatinine is lower than in general

population

Muscle wasting, hypoproteinemia & malnutrition which are

common in cirrhosis contributes to decreased creatinine

production

Serum creatinine production is low in patients with impaired liver

function

Bilirubin interferes with creatinine estimation

Creatinine clearance – as estimate of GFR – inaccurate

Kher V – Ind. J. Gastro. 1994;13:77-78

Hepatorenal Syndrome

Progressive decline in renal function in a patient with cirrhosis

Characterized by renal failure & disturbance in circulatory function

Diagnosis of exclusion

Poor prognosis

Renal failure caused by intense vasoconstriction of renal circulation ,alterations in cardiovascular function and over activity of sympathetic nervous and renin-angiotensin systems

Severe renal vasoconstriction leads to decrease of GFR

Stage 1 AKI # Stage 2 & 3 AKI #

Close monitoring

Remove risk factors (withdrawal of

Nephrotoxic drugs, vasodilators &

NSAIDs, decrease / withdrawal of

Diuretics, treatment of infections* When diagnosed), plasma volume

Expansion in case of hypovolemia

Withdrawal of diuretics

(if not withdrawn Already) & volume

Expansion with albumin

(1 g/kg) for 2 days

Resolution stable progression

Close follow up

Response

Yes NO

Meets criteria of HRS

No Yes

Further treatment of AKI

decided on a case-by-case

basis

Specific treatment for

other AKI phenotypes Vasocontrictors &

albumin

Paolo A et al. Journal of Hepatology 2015 vol 62; 968-974

Proposed algorithm for the management of AKI according to (ICA-AKI)

International Ascites Club (IAC) proposed diagnostic criteria for hepatorenal syndrome -

2015 Criteria Cirrhosis with ascites

Serum creatinine >1.5 mg/dl

No improvement of serum creatinine (decrease to a level of <1.5) after at least 2 days with diuretic withdrawal & volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day

Absence of shock

No current or recent treatment with nephrotoxic drugs

Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhaematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography

Based upon the rapidity of the decline in kidney function, two forms

Type 1 hepatorenal syndrome

- rapid progressive renal failure

- doubling of serum creatinine in less than two wks

- may appear spontaneously but often develops after precipitating event

- Prognosis of type-1 HRS is very poor

Type 2 hepatorenal syndrome

- slowly progressive course

- moderate renal failure (sr.creatinine from 1.5 to 2.5 mg/dl)

- ascites that is resistant to diuretics.

Hepatorenal Syndrome

Pathophysiology of HRS

Pathophysiological hallmark -vasoconstriction of renal circulation

Arterial underfilling in systemic circulation due to arterial vasodilatation in splanchnic circulation

Four interrelated pathways implicated in HRS are:

– Peripheral arterial vasodilation with hyperdynamic circulation & subsequent renal vasoconstriction

– Stimulation of the renal sympathetic nervous system (SNS)

– Cardiac dysfunction which contributes to circulatory derangements & renal hypoperfusion

– Action of cytokines & vasoactive mediators on renal circulation & other vascular beds

Hani M et al. Clin J Am Soc Nephrol2006; 1: 1066–1079.

Pathophysiology

Arterial vasodilatation -central role in hemodynamic changes & decline in renal function in cirrhosis

Role of

– Nitric oxide

– Bacterial translocation from intestine into mesenteric lymph nodes

– cytokines like TNF-alpha & IL-6-

vasodilatation of the splanchnic arterial vessels

Norfloxacin -reduces bacterial translocation

– may improve the hemodynamic abnormalities in cirrhosis

Pere Gines, Robert W Schrier Renal Failure in Cirrhosis. NEJM 2009; 361:1279-90

Precipitating factors

Drugs -aminoglycosides, non steroidal anti inflammatory drugs

Bacterial infection

Gastrointestinal bleeding

Large volume paracentesis without albumin administration

Diuretics

– considered as precipitant of HRS, but diuretics do not cause hepatorenal syndrome

– diuretics causes azotemia when fluid is removed too rapidly in patients without peripheral edema

– Improves with cessation of therapy & fluid repletion

Management

Precipitating factors - actively sought and treated (not graded)

Nephrotoxic drugs - NSAIDS, aminoglycosides

– avoid in patients with or at risk of developing HRS (1C)

Contrast agents – avoid/minimize to reduce contrast induced kidney injury (1D)

Assessment of intravascular volume

Recommendations

Avoid fluid overload (also causes dilutional hyponatremia) (1D)

CVP and PCWP measurement -not reliable markers for predicting intravascular volume (1C)

Techniques like IVC diameter, esophageal doppler, right ventricular end diastolic volume index, left ventricular end diastolic index are used but experience in cirrhosis is limited

Fluid resuscitation in HRS

Albumin infusion (initially 1g of albumin/kg , maximum 100 g followed by 20–40 g/day) in combination with vasopressor therapy (1A) for 14 days is recommended (2D)

Paracentesis

Symptomatic relief in patients with increased intra abdominal pressure

Future studies required to investigate the effect of reducing intra- abdominal pressure on renal function

Management

Pharmacological treatment of HRS

Bridge to liver transplantation- otherwise

prognosis is poor

Splanchnic vasodilatation - central role in

pathogenesis of HRS- vasoconstrictors widely

used in treatment of Type1 HRS

Terlipressin

Vasopressin & its analogs (ornipressin & terlipressin) reduces splanchnic vasodilatation (preferential effects on V1 receptor ) – intravenous bolus 1 to 2 mg every 4 to 6 hours along

with bolus albumin for 2 weeks – A/E-ischemia ,increases cardiovascular adverse

events – expensive drug

Norepinephrine (noradrenaline)

– potent vasoconstrictor of both venous and arterial vasculature

– can be administered to patients who cannot afford terlipressin (in ICU setting)

Octreotide and midodrine

Midodrine - systemic vasoconstrictor

Octreotide - long-acting somatostatin analogue, inhibits endogenous vasodilator release thus causes splanchnic vasoconstriction

Used when terlipressin not available

Octreotide 100– 200mcg s/c & midodrine 7.5 -12.5 mg thrice daily along with albumin

Treatment HRS

Recommendations

Type 1 HRS- treated with albumin (initially 1 g/kg of body

weight for 2 days, maximum of 100 g/day, followed by

(20 - 40 g/day) in combination with a vasoconstrictor (1A)

preferentially terlipressin (2C)

If terlipressin not available, norepinephrine or combination

of octreotide & midodrine, together with albumin should be

considered (2C)

Duration of therapy - 2 weeks

TIPS Transjugular intrahepatic portosystemic shunt

Treatment of refractory ascites

last resort

Associated with complications

- deterioration of liver function

- worsening of hepatic encephalopathy

- risk of bleeding associated with procedure

- contrast nephropathy

Dialysis

HRS patients awaiting transplantation

Hemodialysis - difficult in these patients due to

hemodynamic instability

CRRT (Continuous renal replacement therapy) preferred

SLED good alternative

Liver Transplantation

Treatment of choice for both type1 and 2 HRS

Morbidity after liver transplantation is higher in

patients with HRS than those without HRS

Liver allocation based on MELD score

MELD Score

In 2003, model for end-stage liver disease (MELD)

score was proposed as a better, simple alternative

to Child–Pugh score

Three variables

- serum bilirubin

- international normalized ratio (INR)

- serum creatinine

Patients with high pre-transplant creatinine have a higher MELD score so more rapid access to

transplantation. Wiesner R et al. Gastroenterology 2003;124: 91–96.

Combined liver and kidney Transplantation (CLKT)

CLKT number- increased since implementation of MELD score-based allocation system

Pre-transplant dialysis in ARF -not an indication for kidney transplantation

Dialysis dependent patients for ≥ 8 weeks & if renal recovery not possible should be considered for CLKT

Chronic kidney disease patients with GFR below 30 ml/min

Borderline patients – biopsy

– CLKT preferred to liver transplantation alone when more than 30% glomerulosclerosis and/or more than 30% interstitial fibrosis

Ruiz R et al. Liver Transplant 2007;13: 838–843