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Hepatorenal Syndrome

ICD-9 572.4

3 main components: altered liver function, abnormalities in circulation, and renal failure
Liver pathology is altered, kidney histology is normal
rapid deterioration in kidney function in pts with cirrhosis/fulminant liver failure
usu fatal unless liver transplant, dialysis can prevent advancement

mc etio: cirrhosis
severe alcoholic hepatitis, fulminant hepatic failure
portal hypertension
occurs when liver fx deteriorates rapidly dt acute injury: infx, GI bleed, diuretic overuse
relatively common complication of cirrhosis
occurs in 18% of cirrhotics within one yr of dx, in 39% w/in 5yrs of dx

bacterial infection, acute alcoholic hepatitis
bleeding in the upper gastrointestinal tract
mc trigger in cirrhotic individuals: spontaneous bacterial peritonitis
iatrogenic triggers:
aggressive use of diuretic medications
large volume paracentesis without intravenous fluid replacement

Type 1 HRS
rapidly progressive decline in kidney function
doubling of serum creatinine to a level greater than 221 μmol/L (2.5 mg/dL)
or a halving of the creatinine clearance to less than 20 mL/min
over a period of less than two weeks
prognosis: grim, mort rate exceeding 50% after one mo
pts usu ill, mb hypotensive
need inotropes to keep heart strong and vasopressors to maintain BP

Type 2 HRS
associated with diuretic resistant ascites
slower in onset and progression
defined: creat >133 μmol/L (1.5 mg/dL) or CCLR <40 mL/min
urine sodium < 10 μmol/L
prog: poor, median survival ~6mo w/o liver transplant
thought to be part of a spectrum of illness assoc w portal HTN-->ascites-->diuretic resistance
kidneys unable to excrete sufficient sodium to clear the fluid
diuretic resistant ascites usu precedes type 2 HRS

high risk
type 1 HRS over 50% over the short term, as determined by historical case series
complications: spontaneous bacterial peritonitis, GI hemorrhage

decr liver fx-->INCR renal vessel tone, DECR splanchnic vessel tone-->hypoperfusion injury
kidney histology is normal
kidneys function normally when tranplanted into pt with healthy liver

predominant theory (underfill theory)
dilated splanchnic circulation-->vasoconstrx renal circ
Abn substances usu cleared by liver may cause general dilatation of bvs in body-->hypotn
usu grad onset dt heart compensation
No tx for this hypotn except general supportive care, transplant
vasodil except kidney where they are intensely constricted
hypothetically mediated by factors released by liver dz: Nitric oxide, prostaglandins, atrial natriuretic factor, prostacyclin, thromboxane A2, endotoxin, other vasoactive substances
also involved: epi and norepi balance, renin-angiotensin-aldosterone system
"sinusoidal htn induces systemic vasodil and reduces systemic vasc resistance"
"splanchnic vasodil leads to a forward incr in filtration across splanchnic capillaries"
(Rossle 2010 article in Gut)

decr flow to juxtaglomerular apparatus-->secretion of renin-->RAA system activated
-->vasoconstrx systemically and in the kidney specifically
overall decreased systemic vascular resistance in hepatorenal syndrome
femoral and renal fractions of CO respectively increased and reduced
*meds to tx splanchnic vasodilation (ornipressin, terlipressin, octreotide)-->improved GFR
the RAA effect insuff to counteract splanchnic vasodilation
-->persistent "underfilling" of renal circ, worsening renal vasoconstrx-->renal failure
(RAA system-->aldosterone--> should incr adsorption of Na from DCT)

majority of individuals with HRS have cirrhosis
~10% of ascites hospital admits

retrospective case series of cirrhotic patients txd with terlipressin
-->20.0% of acute renal failure in cirrhotics was due to type 1 HRS
6.6% was due to type 2 HRS

study of renal failure (RF) in ps with cirr revealed frequency of 32% infection-induced RF, 24% parenchymal renal disease, 22% preRF, 11% ATN, 8% HRS, and 3% nephrotoxic RF

est 18% of individuals with cirrhosis and ascites will develop HRS within one year of their diagnosis with cirrhosis, and 39% of these individuals will develop HRS within five years of diagnosis

Three independent risk factors for the development of HRS in cirrhotics have been identified: liver size, plasma renin activity, and serum sodium concentration

altered mental status
evidence of decreased nutrition
ascites (resistant to diuretics = type 2)
possible oliguria or normal urine volume

not clinical, purely laboratory and exclusion of other causes
*renal dysfx mb missed in cirr pts dt low mm mass-->lower creat even w/ low GFR

(all must be present)
advanced liver dz in the setting of portal hypertension
low GFR (CCLR<40mL/min or creat >1.5mg/dL)
absence of shock, sepsis, nephrotoxins, volume depletion
absence of sustained improvement in renal fx (to creat>1.5 or CCLR>40) following diuretic withdrawal and 1.5L IV normal saline
absence of proteinuria (<500mg/dL)
absence of renal disease or obstx (US)

(not necessary but supports dx)
low urine volume (<500 mL/day)
urine Na <10mEq/L
urine osmolality greater than blood osmolality
urine RBCs <50/hpf
serum sodium <130 mmol/L
usu no casts in urine

pre-renal failure (has hyponatremia too but responds to tx with IV fluids)
acute tubular necrosis (ATN) esp dt meds (urine sodium is higher or normal unless cirrhotic)
(may have hyaline casts, muddy-brown casts)
hepatitis B and C can-->inflam of glomerulus
drug toxicity (gentamicin, contrast, acetaminophen, acetylsalicylic acid, CoCl4)
Granulomatous diseases (sarcoidosis, drug-induced)
Infx: malaria, leptospirosis
Infiltrative: amyloidosis
Inflam: lupus, Sjogren's syndrome
Nonalcoholic fatty liver disease and diabetic nephropathy
Preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelets)
Polycystic kidney/liver disease (autosomal dominant/autosomal recessive forms)
Sickle cell disease
Shock states (congestive heart failure, sepsis, hypovolemia

Fluid losses -- vomiting, diarrhea, diuretic use .
Gastrointestinal bleeding
Infection -- fever, cough, dysuria, abdominal discomfort
Exposure to nephrotoxins -- drugs (aminoglycosides, NSAIDs), radiocontrast agents
HR, BP, orthostatic, temp
infx? pulm, abd, cellulitis
Other causes of renal failure? purpuric rash may suggest cryoglobulinemia
(types 2 and 3 cryo strongly assoc w/ hep c http://en.wikipedia.org/wiki/Cryoglobulinemia)
CBC, electrolytes, creat
urine: Na, osmolality, prot, cells, casts
Renal ultrasound

avoid spontaneous bacterial peritonitis) and gastrointestinal hemorrhage
identify and tx risks
avoid aggressive use of diuretic medications
avoid large volume paracentesis and give albumin on day 1 & 3 if any paracentesis
possible for paracentesis to relieve pressure on renal aa and improve fx

ABX prophylaxis vs bact infx in pts c GI bleeds or hx of SBP
Postparacentesis IV albumin to maintain volume
Judicious Use of Diuretics (20% of ascites pts get diuretic induced renal impairment)
Avoid Nephrotoxic Agents (aminoglycosides, NSAIDS, ACE inhibitors, ARBs)

liver transplant is only longterm tx
meds to improve abn vessel tone
liver dialysis (new extracorporeal liver support): dialysis circuit w alb-bound membranes to bind/remove toxins normally cleared by the liver

definitive treatment: orthotopic liver transplantation
mort 25% in 1st mo after transplant: worse than pts w/o HRS
pt w end-stage liver disease scores above 36 at greatest risk
further deterioration of renal fx may occur, transient, usu dt nephrotoxic immunosuppressants
(tacrolimus and cyclosporine)
if survive liver transplants-->almost universally recover kidney function
survival rates at three years are sim to those w transplant for other reasons

intravenous albumin infusion
medications (best evidence for analogues of vasopressin-->splanchnic vasoconstriction)
TIPS: radiological shunts to decrease pressure in the portal vein
specialized albumin-bound membrane dialysis system termed molecular adsorbents recirculation system (MARS) or liver dialysis

one cited regimen is 1 gram of albumin per kilogram of body weight IV on day 1
followed by 20 to 40 grams daily
treatment with albumin alone is inferior to combo tx

Midodrine (oral) = alpha-agonist, vasoconstrx
octreotide = analogue of somatostatin, inhibits splanchnic vasodil
dosing based on BP
not useful individually but may be helpful used together
incr survival at 30 days

Dopamine 2-4 mcg/kg/min IV

ornipressin = vasopressin analogue, useful but may cause severe ischemia to major organs

Terlipressin = vasopressin analogue, also nonselective V1 vasopressin agonist
one large study sez less ichemia
improves renal fx in pts with type I HRS and improved survival
One suggested protocol consists of 0.5 mg every 4 hours with a titration upward by 0.5 mg every 3 days up to 2 mg every 4 hours

Endothelin antagonists

also tried:
pentoxifylline (used in pts with alc hep)


transjugular intrahepatic portosystemic shunt
decompression of the high pressures in the portal circ
theory: decr portal pressure-->reverse vasodil/vasoconstrx paradox and HRS
does improve renal function, perfusion
rapid increase in urinary Na excretion, urine volume, improved plasma creatinine
gradual improvement of renin, aldosterone and noradrenaline levels
95% success in reducing portal HTN
first used as bridge to transplant but now used in some non-transplant pts
does not improve liver fx, not permanent fix

small stent between a portal and hepatic vein
radiologically guided catheters iva int jugular or femoral vein
provides portal between high P before liver to low P after liver (bypasses liver)
Tract made by inserting catheter via jugularbvs draining liver, install shunt thru hep tissue to drain portal vein into systemic circ
Inflate balloons, inserve wire mesh stent

Complic: worse hepatic encephalopathy, liver failure, persistent portal HTN, bleeding
Tips devices also used in gastric or esophageal hemorrhage, ascites, and hepatorenal syndrome

NEW extracorporeal dialysis
remove toxins from the circulation
addition of a second dialysis circuit that contains an albumin-bound membrane
molecular adsorbents recirculation system (MARS)
believed that this system removes vasoactive substances that cause HRS

Improvement of hepatorenal syndrome with extracorporeal albumin dialysis mars: Results of a prospective, randomized, controlled clinical trial
Stefan R. Mitzner*, et al. at *Department of Medicine, U of Rostock, USA and Depts of Med and Surgery, Eberhard Karls U of Tübingen, Germany
Available online 15 July 2005.
In hepatorenal syndrome (HRS), renal insufficiency is often progressive, and the prognosis is extremely poor under standard medical therapy. The molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. MARS enables the selective removal of albumin-bound substances. A prospective controlled trial was performed to determine the effect of MARS treatment on 30-day survival in patients with type I HRS at high risk (bilirubin level,15 mg/dL) compared with standard treatment. Thirteen patients with cirrhosis with type I HRS were included from 1997 to 1999. All were Child's class C, with Child-Turcotte-Pugh scores of 12.4 ± 1.0, United Network for Organ Sharing status 2A, and total bilirubin values of 25.7 ± 14.0 mg/dL. Eight patients were treated with the MARS method in addition to hemodiafiltration (HDF) and standard medical therapy, and 5 patients were in the control group (HDF and standard medical treatment alone). None of these patients underwent liver transplantation or received a transjugular intrahepatic portosystemic shunt or vasopressin analogues during the observation period. In the MARS group, 5.2 ± 3.6 treatments (range, 1 to 10 treatments) were performed for 6 to 8 hours daily per patient. A significant decrease in bilirubin and creatinine levels (P < .01) and increase in serum sodium level and prothrombin activity (P < .01) were observed in the MARS group. Mortality rates were 100% in the control group at day 7 and 62.5% in the MARS group at day 7 and 75% at day 30, respectively (P < .01). We conclude that the removal of albumin-bound substances with the MARS method can contribute to the treatment of type I HRS.

only offer in select cases w real chance of liver transplantation in the short term.
fraught with difficulties dt coagulopathy, hemodynamic instability, risk of sepsis
effectiveness for HRS not proven
depends on condition of pt
used to avoid complications of renal failure until transplantation
inadequate research so far


Thorne: TAPS: flavonoid phytosomes for enhanced absorption
silybin and curcumin complexed w phosphatidylcholine, and hepatoprotective picrorhiza


TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update, Rossle, Martin and Gerbes, Alexander, Gut 2010;59:988-1000. doi:10.1136/gut.2009.193227. Available online at: http://gut.bmj.com/content/59/7/988.short?rss=1




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