HEPATORENAL SYNDROME

Systemic Diseases Involving Both Liver and Kidney

Drug toxicity -- acetaminophen, acetylsalicylic acid, carbon tetrachloride, etc. Granulomatous diseases (sarcoidosis) Infectious -- malaria, leptospirosis Infiltrative amyloidosis Inflammatory -- lupus, Sjogren's syndrome Nonalcoholic fatty liver disease and diabetic nephropathy Preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome Polycystic kidney/liver disease (autosomal dominant/autosomal recessive forms) Sickle cell disease Shock states (congestive heart failure, sepsis, hypovolemia)

Hepatitis B

Membranous glomerulonephritis (GN), essential mixed cryoglobulinemia.

Hepatitis C

Membranoproliferative GN, membranous GN, cryoglobulinemia, fibrillary GN, IgA nephropathy, tubulointerstitial nephritis IgA nephropathy Prerenal azotemia/acute tubular necrosis from hypovolemia, decreased cardiac output, sepsis; acute tubular necrosis from toxic bile acids

Alcoholic liver disease Obstructive jaundice

Primary biliary cirrhosis

Membranous GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, antiglomerular basement membrane disease, renal tubular acidosis, tubulointerstitial nephritis
Membranous GN, membranoproliferative GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, tubulointerstitial nephritis Renal tubular acidosis (Type 1) secondary to copper deposition

Primary sclerosing cholangitis Wilson's disease

Alpha-1 antitrypsin deficiency

Membranoproliferative GN, antiglomerular basement membrane disease

Hepatorenal syndrome (HRS)

Hepatorenal syndrome is a functional and reversible form of renal failure that occurs in patients with advanced chronic liver disease (in absence of other identifiable cause of renal pathology). (Gut 2001)

The distinctive hallmark feature of HRS is intense renal vasoconstriction caused by interactions between systemic and portal hemodynamics: decreased effective arterial volume and activation of vasoconstrictor systems

 Absence of histological changes in renal tissue Preserved renal tubular function Histologically, kidneys are normal Renal functions can be restored when kidneys are removed and transplanted into non-cirrhotic recipient.

INCIDENCE

Cirrhotic patients admitted to medical ICU have increased mortality (40 to 90%) and a poor prognosis.
80% of hospitalized patients with cirrhosis and ascites have decreased renal perfusion due to moderate vasoconstriction in renal circulation, which predisposes them to HRS. Annual incidence : 8-40% in cirrhosis
(Clin Gastroenterol hepatol 2006)

INCIDENCE
Annual incidence between 8% and 40% in cirrhosis depending on the MELD score
The frequency of HRS in severe acute alcoholic hepatitis and in fulminant liver failure is about 30% and 55%, respectively

Munoz S. Medical Clinics of North America July 2008

Predictors for development of HRS

 A multivariate analysis disclosed only 3 independent predictors of hepatorenal syndrome occurrence: 1) Hyponatremia 2) high plasma renin activity 3) absence of hepatomegaly (Gastroenterology 1993)

Diagnostic criteria (major)

All must be present:
International ascites club, 1996

Advanced hepatic failure and portal hypertension (acute/chronic) Low GFR defined as serum creatinine >1.5mg/dl or cr. Cl < 40ml/min Absence of shock, significant volume losses, ongoing infection, or nephrotoxic agents ( diagnosis of exclusion) Absence of sustained improvement in renal function after intravenous saline infusion (1.5L of isotonic fluids) and cessation of diuretics

Proteinuria < 500mg/day with no USG evidence of obstruction or parenchymal renal disease
Arroyo et al. Hepatology 1996

Additional criteria (supportive evidence)

Urine volume < 500ml/day Urine sodium < 10mEq/L Urine osmolality > plasma osmolality Urine RBCs < 50/hpf Serum sodium < 130mEq/L

Arroyo et al. Hepatology 1996

A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in SBP. (Hepatology 2005)
The administration of albumin improves circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
Albumin vs HES , n=10 (ALBUMIN), n=10 ( HES)

Baseline measurements were performed within 12 hours after diagnosis of infection.

Patients then received 2 doses of volume expander (1.5 g/kg body weight after baseline measurements and 1 g/kg body weight on day 3).

Treatment with albumin was associated with significant increase in arterial pressure and suppression of plasma renin activity, indicating an improvement in circulatory function. In contrast, no significant changes were observed in these parameters in patients treated with hydroxyethyl starch.

PATHOGENESIS OF HRS

CLASSICAL PERIPHERAL ARTERIAL VASODILATION HYPOTHESIS

Survival probability

Nitric oxide
Nitric oxide (NO) is a potent vasodilator that is elevated in the peripheral circulation of patients with cirrhosis The imbalance between NO and vasoconstrictors such as endothelin-1 in the renal microcirculation has been proposed to be responsible for the progressive deterioration in kidney function in these patients

Kayali et al. Journal of Gastroenterology and Hepatology February 2009

 Nitric oxide has a very short half-life; therefore, measurement of the NO metabolites, nitrite and nitrate (NOx), are commonly used to estimate NO levels in the circulation Because both metabolites are excreted predominantly by the kidney, decreased renal clearance rather than overproduction could account for the elevated level of NOx in decompensated cirrhosis

Kayali et al. Journal of Gastroenterology and Hepatology February 2009

 L-Arginine (L-Arg), a nonessential amino acid, is the precursor for NO production by nitric oxide synthase The liver is the major site for arginine metabolism, where arginine generated in the urea cycle is rapidly converted to urea and ornithine by arginase-1 NOS and arginase-1 compete for available arginine and it is possible that the overproduction of NO results from an excess availability of substrate

Kayali et al. Journal of Gastroenterology and Hepatology February 2009

 Patients with either compensated cirrhosis, cirrhotic patients with ascites, refractory ascites (RA) or chronic hepatorenal syndrome (HRS) type II were included in the sudy Normal healthy volunteers, organ donors and chronic renal failure (CRF) patients without liver disease were included as controls

Kayali et al. Journal of Gastroenterology and Hepatology February 2009

 After adjusting for all demographics and variables, HRS was the only disease state predicting high levels of NOx in the peripheral circulation (P < 0.001) Multivariate analysis also revealed that HRS was an independent factor predicting high levels of L-Arg (P = 0.03) Chronic renal failure and stages of progressive renal dysfunction in decompensated cirrhosis were not independently associated with peripheral levels of NOx or L-Arg Peripheral levels of NOx reliably reflect NOx levels in the splanchnic circulation, suggesting that peripheral levels of NOx can be used diagnostically as a marker for disease state

Kayali et al. Journal of Gastroenterology and Hepatology February 2009

Assessing kidney function in pts with cirrhosis

Cr assays are subject to interference by chromogens, bilirubin being the major one There is decreased hepatic production of creatine The edematous state that complicates end-stage liver disease leads to large distribution of Cr in the body and lower serum Cr concentration Complications such as variceal bleeding, spontaneous bacterial peritonitis or sepsis lead to increased Cr tubular excretion

Proulx et al. Nephrology Dialysis Transplantation 2005

Pre-renal
Urine Na (mmol/L) Proteinuria (mg/day) Urine sediment <10

ATN
>20

HRS
<10

Primary renal
>30

nil bland

<500 granular

<500 nil

>500 RBC/WBC casts

Urine Cr/plasma Cr
Precipitants

>20

<15

>30

< 20

Decreased EAV (effective arterial vol) Immediate improveme nt

Decreased EAV, nephrotoxic agents, sepsis maintain euvolemia

Advanced liver disease, refractory ascites, UGIB, SBP nil

Dependent on type of renal disease

Volume Expansion

Must maintain euvolemia

Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis
Acute kidney injury :Rise in serum creatinine of 50% from baseline or a rise of serum creatinine by 26.4 mmol/l (0.3 mg/dl) in <48 h HRS type 1 is a specific form of acute kidney injury
Chronic kidney disease :Glomerular filtration rate of <60 ml/min for >3 months calculated using MDRD6 formula HRS type 2 is a specific form of chronic kidney disease Acute-on-chronic kidney disease :Rise in serum creatinine of 50% from baseline or a rise of serum creatinine by 26.4 mmol/l (0.3 mg/dl) in <48 h in a patient with cirrhosis whose glomerular filtration rate is <60 ml/min for>3 months calculated using MDRD6 formula

Classification of the hepatorenal syndrome

Type 1: cirrhosis with rapidly progressive acute renal failure Type 2: cirrhosis with subacute renal failure Type 3: cirrhosis with types 1 or 2 HRS superimposed on chronic kidney disease or acute renal injury Type 4: fulminant liver failure with HRS

Munoz S. Medical Clinics of North America July 2008

Type1 HRS
Acute, progressive and severe renal failure Very poor, short-term outcome ( < 2weeks survival; without liver transplantation). 100% increase/doubling of serum creatinine to >2.5mg/dl , or 50% reduction of initial 24hr creatinine clearance to less than 20ml/min in < 2weeks Ass. with SBP (spontaneous bacterial peritonitis), precipitating factors Pattern: AKI
Arroyo et al. Hepatology 1996

Type 2 HRS
Steady decline of renal function
Survival time(= approx.6months) longer than type 1 HRS serum creatinine >1.5 mg/dl resistant to diuretic therapy & ass. with refractory ascites (requiring paracentesis)

Pattern: CKD
Arroyo et al. Hepatology 1996

Type 3 hepatorenal syndrome

85% of end-stage cirrhotics have intrinsic renal disease on renal biopsy Patients with long-standing diabetic nephropathy, obstructive renal disease, or chronic glomerulonephritis can develop HRS from a precipitating event or worsening liver failure

Munoz S. Medical Clinics of North America July 2008

Type 4 hepatorenal syndrome

More than half of patients with ALF develop HRS, although the frequency varies depending on the ALF etiology The pathophysiology of HRS in ALF is believed to be similar to that postulated for HRS occurring in cirrhosis

Munoz S. Medical Clinics of North America July 2008

Work-up for Patients With Suspected HRS Table 4 History

Fluid losses -- vomiting, diarrhea, diuretic use . Gastrointestinal bleeding Infection -- fever, cough, dysuria, abdominal discomfort Exposure to nephrotoxins -- drugs (aminoglycosides, NSAIDs), radiocontrast agents

Physical exam
Heart rate, blood pressure (including orthostatic), temperature Signs of infection (pulmonary, abdominal, cellulitis, etc.) Other causes of renal failure -- purpuric rash may suggest cryoglobulinemia

Investigations

Complete blood count, electrolytes, creatinine level Urine sodium, osmolality Urinalysis for protein, cells, and casts Renal ultrasound

PREVENTION OF HRS
Bed rest and to follow a low-sodium diet (60 to 90 mmol/day, equivalent to about 1.5 to 2 g of salt per day). Spironolactone is prescribed at increasing doses (100 mg/day as initial dosages;if there is no response within 4 days, 200 mg/day; if no further response, 400 mg/day). Furosemide is added at increasing dosages every 2 days (40 to 160 mg/day). Therapeutic paracentesis, when it is combined with plasma volume expansion using albumin (8 g per liter of ascites removed),is helpful and is associated with a low incidence of circulatorydysfunction after treatment.

Prevention of HRS
1) Volume expansion: - albumin (1.5 g/kg IV) at diagnosis and at (1 g/kg IV) day 3 in patients with SBP significantly reduces incidence of type1 HRS and 3-month mortality. (NEJM 1999) 2) Avoidance of nephrotoxic drugs 3) Pentoxifylline - 400 mg three times a day orally for 4 weeks in patients with severe acute alcoholic hepatitis ( Gastroenterology 2000) 4) Antibiotic Prophylaxis SBP , UGIB
(Gastroenterology 2007)

Albumin
Albumin (1.5 g/kg iv at infection diagnosis and 1 g/kg iv 48 hours later) to patients with cirrhosis and SBP : markedly reduced the incidence of circulatory dysfunction and type 1 HRS 3-month mortality rate was lower in patients receiving albumin.
Navasa et al 1999

Pentoxifylline improves short-term survival in severe alcoholic hepatitis: A double-blind, placebo-controlled study
n =101 with severe, alcoholic hepatitis (DF>32) pentoxifylline, 400 mg three times a day orally for 4 weeks (study arm) Placebo (vit B12) for 4 weeks (control arm)

RESULTS: Decreased mortality, RR=0.59 Decreased incidence of HRS, RR=0.29

( Gastroenterology 2000)

 The first study was performed in cirrhotic patients with a high risk of developing SBP and type-1 HRS . Primary prophylaxis of SBP, using long-term oral norfloxacin, was given to patients with low protein ascites of15 g/l and serum bilirubin of 3 mg/dl or serum creatinine of 1.2 mg/dl. Significant decrease in the 1-year probability of developing SBP (7 vs. 61%) and type-1 HRS (28 vs. 41%) 3-month and 1-year probabilities of survival(94 vs. 62 and 60 vs. 48%, respectively).
Navasa M, Fernandez J, J Hepatol 2006;44:S51

EASL practice guidelines journal of hepatology 2010

Patients who recover from an episode of SBP have high risk of recurrent SBP. In these patients, administration of prophylactic antibiotics reduces the risk of recurrent SBP. Noroxacin (400 mg/day, orally) is the treatment of choice (Level A1).
Alternative antibiotics include ciprooxacin (750 mg once weekly,

orally) or co-trimoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim daily, orally), but evidence is not as strong as that with noroxacin (Level A2).

Specific management of HRS

Liver transplantation Vasoconstrictors + albumin

TIPS

Specific management of type1 HRS

PHARMACOLOGICAL: Vasopressin analogues ( vasopressin, ornipressin, terlipressin) Somatostatin analogues - octreotide Alpha agonists- midodrine, noradrenaline Albumin Misc. drugs (dopamine, endothelin antagonists, etc) NON-PHARMACOLOGICAL: TIPS RENAL SUPPORT MARS LIVER TRANSPLANT
vasoconstrictors

Vasopressin Analogues: Vasopressin, Terlipressin (Glypressin):

Terlipressin (Glypressin): Most widely used vasopressin analogue Longer half life - 2-10 hours, less ischemic side effects Several uncontrolled studies support its use in Type 1 HRS

Patients treated successfully with albumin and terlipressin before liver transplantation have outcomes after transplantation , similar to those without HRS.

Terlipressin
Terlipressin, an agonist of the V1 vasopressin receptors, is inactive in its native form, but is transformed into the biologically active form, lysine-vasopressin through enzymatic cleavage of glycyl residues by tissue peptidases Because of this modification, terlipressin has a prolonged biological half-life compared with other vasopressin analogues

Terlipressin: Meta Analysis

Five studies involving 243 patients with HRS were identified Pooling of study results showed a significant increase in HRS reversal among patients who received terlipressin versus those who received placebo (the pooled odd ratio OR of HRS reversal was 8.09 p=0.0001) The rate of severe ischemic events was higher in study than control patients, (pooled OR=2.907 p=0.032) Terlipressin use had no significant impact upon survival (pooled OR for survival rate, 2.064 p=0.07)

Fabrizi et al. The International Journal of Artificial organs March 2009

Terlipressin: Int Urol Nephrol (2011) 43:175184

midodrine + octreotide
Midodrine Oral, 1 agonist (arteriolar and venous constriction) Increases BP Increases renal perfusion

Octreotide
Somatostatin analogue IV/s.c route Inhibitor of endogenous vasodilators(glucagon,VIP) Decreases portal pressure Splachnic vasoconstriction Increases GFR

midodrine + octreotide
3 clinical trials results comparable to those reported for terlipressin In 2 of these studies, intravascular volume supported with albumin (Hepatology 1998,2004) In a recent report of 81 patients treated with midodrine-octreotide (without concurrent albumin)
40% of patients responded with sustained reduction in serum creatinine, and the 30-day survival was 57%, significantly superior to the 30% survival of controls . (Estrailian et al)

Noradrenaline
Noradrenaline, in combination with albumin, has also been shown to be as effective as terlipressin .
( hepatology 2002)

But, used only in few studies. Larger trials needed.

Contraindications to vasoconstrictors
Coronary artery disease Peripheral vascular disease Cardiomyopathies Arrhythmias Hypertension Cerebrovascular accident Age >70 Asthma Terminal liver disease Advanced hepatocellular carcinoma

miscellaneous drugs
Dopamine ( as renal vasodilator) Misoprostol (PGE1 analogue - renal vasodilator) Endothelin antagonists (tezosentan) N-acetylcysteine

Limited role of all above therapies.

TIPS (transjugular intrahepatic porto-systemic shunt)

Decompresses portal circulation, thereby, lowering portal pressures

Splanchnic volume returned to systemic circulation.

Increases effective arterial volume (EAV)

Downregulates RAAS

Prohibits renal vasoconstriction.

Bridge to liver transplantation in HRS type1 Experimental therapy

(Brensing. GUT 2000)

TIPS

n=21, type1 HRS n=20, type2 HRS 10 excluded 31 received TIPS Renal function & survival analyzed Conclusions: TIPS
reduced portal pressure gradient (p<0.05) improved renal function and survival Controlled trials needed

 TIPS is of investigatory use for the treatment of hepatorenal syndrome (HRS), especially type1, pending the publication of controlled trials (Grade II recommendation).
(AASLD Guidelines. Hepatology 2010)

Dialysis
Dialysis should only be offered in select cases if there is a real chance of liver transplantation in the short term.
Dialysis in these patients is fraught with difficulties because of coagulopathy , hemodynamic instability, and risk of sepsis. Continuous hemofiltration (CVVHD) preferred because of the labile blood pressure in these patients.

The effectiveness of dialysis in treatment of HRS has not been proven.

(Witzke et al.2004)

 CRRT is better tolerated than IHD in patients with liver failure as evidenced by better cardiovascular stability, gradual correction of hyponatremia, and less fluctuation in intracranial pressure. CRRT has the potential advantage of removing inflammatory cytokines, including TNF- and IL-6

 From 1985 to 1995, 10 patients received preoperative RRT (all HD) and their 1-yr survival after transplantation was 89.5%. From 1996 to 1999, a total of 19 patients also received preoperative RRT: One HD and 18 CRRT; the 1-yr patient survival in this group was lower, at 73.6%, possibly reflecting the more serious nature of their illness.

 102 patients who had cirrhosis and ARF, 48% of them with HRS, and were awaiting a liver transplant and receiving RRT showed increased mortality for those who were maintained on CRRT compared with HD (78 versus 50%; P = 0.02)

Kidney Int68 :362 370,2005

MARS (molecular adsorbent recirculating system)

use of an albumin-containing dialysate circuit, which is connected to a conventional dialysis apparatus.

removal of albumin-bound substances and toxins, including

ammonia, bile acids, medium-chain fatty acids, copper, NO, TNF

bridge to liver transplantation. limited experience

( Crit Care Med 2001)

Extracorporeal-albumin-dialysis

MOLECULAR ADSORBENT RECIRCULATING SYSTEM

 MARS improved clinical and biochemical parameters as well as survival in eight patients who had type 1 HRS and were not candidates for TIPS insertion compared with a wellmatched group of patients who were treated with volume expansion and CRRT Mean survival of 25 days compared with 4.6 days in the control group
prospective, randomized, controlled clinical trial. Liver Transpl6 :277 286,2000

 8 patients with type 1 HRS and alcoholic hepatitis were treated with MARS and showed improvement in urine volume, mean arterial BP, encephalopathy grade, and Child-Pugh score . Five patients survived >12 mo, with only one patient requiring a liver transplant 18 months after therapy
Ther Apher5 :417 422,2001 Mitzner SR

OLT
Liver transplantation remains the best treatment for suitable candidates with HRS because it offers a cure to both the diseased liver and the renal dysfunction. Indeed, subsequent to liver transplantation, renal sodium excretion and hemodynamic abnormalities normalize within 1 month, and renal resistive indices decrease to normal values during the first post transplantation year
Hepatology35 :1179 1185,2002