Hepatorenal syndrome
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Transcript of Hepatorenal syndrome
M.Farouk HRS
Hepatorenal Syndrome
Definition
Pathogenesis
Diagnosis
Treatment
Research points
TaKeHoMeMeSsAgEs
ByMohamed Farouk Ali
M.Sc., Specialist of Tropical medicine and Gastoenterology
M.Farouk HRS
M.Farouk HRS
Canwe prevent occurence of HRS?
Canwe predict it’s occurrence?
Canwe diagnose HRS early?
Dowe miss diagnosing some patients with HRS?
Should I Give up,if the patient do not respond to vasopressor therapy?
Hepatorenal SyndromeDefinition
The occurrence of renal failure
in a patient with advanced liver disease
in the absence of an identifiable cause of renal failure. Thus, the diagnosis is essentially by exclusion of other causes of renal failure
Hepatorenal SyndromeDefinition
Functionalproblem
Advanced liver
diseaseAbsence of identifiable
cause
PotentialReversible
July 1956
M.Farouk HRS
The first detailed description of HRSby Hecker and Scherlock
What about the
pathogenesis
?M.Farouk HRS
Story
Advanced
livear diseas
e
Renal vasoconstrictionM.Farouk HRS
NotWell
understood
The Hallmark is
Renal vasoconstriction
M.Farouk HRS
Splanchnic Steal Phenomenon
M.Farouk HRS
Splanchnic Steal Phenomenon
End stage liver disease
Liver cell failure and portal hypertension
Endogenous vasoactive substances
Systemic vasodilatation and mainly splanchnicwith further pooling of blood in the splanchnic region
The thief is the splanchnic vessels&Here the game begins.…
The Body “The police” will act againstLow arterial pressure, reduced effective bl. Vol.
and pooling of blood in the Splanchnic region
Low arterial blood pressure resulting in:Reduced effective arterial blood volume
M.Farouk HRS
incr
easi
ng C
OP
Splanchnic Steal Phenomenon
ADH
Activ
ation
of S
ympa
theti
c ne
rvou
s sy
stem
Activ
ation
of
Reni
n an
giot
ensi
n al
dost
eron
sys
tem
Body’s defence will act against that vasodilatation
not enough to correct the
haemodynamic instabilty
Failed trial
Sometimes,Decreased COP
caused by cirrhotic cardiomyopathy
Endothelin
M.Farouk HRS
Splanchnic Steal PhenomenonSplanchnic region,
Unfortunatelly,will respond poorly to vasoconstrictive mechanisms
Vasoconstriction elsewhere will occur
Renal vasoconstriction
Decreased activity of renal vasodilatory factors:PGs, NO
M.Farouk HRS
Increased release of natreuretic peptidesBut not enough to correct renal vasoconstriction
More splanchnic vasodilataion….More steal of blood from renal vessels…
More renal vasoconstriction…More progress…
Splanchnic Steal PhenomenonRenal vasoconstriction
Kidney Angina
Kidney ischaemia
Impaired renal
function
M.Farouk HRS
This may explain the difference among patientsin the intensity and the course of the disease
Imbalance betweenvasoconstrictors and vasodilators
HRS
Type 2Type 1Moderate, steady renal failure with
a serum creatinine of >1.5 mg/dl.
arises spontaneously and is the main underlying mechanism of refractory ascites.
Rapidly progressive renal failure that is defined by
doubling of initial serum creatinine to a level >2.5 mg/dl
or by 50% reduction in creatinine clearance to a level <20 ml/min
in <2 wk
a precipitating factor frequently is identified
M.Farouk HRS
M.Farouk HRS
If you focus on problems you will have more problemsIf you focus on possibilities you will have more opportunities
Now,
How can I diagnose it
?
M.Farouk HRS
1996 The International Ascites Club
Major criteria
Additional criteria
M.Farouk HRS
2005 The International Ascites Club
New criteria
M.Farouk HRS
2005 The International Ascites Club
1.Cirrhosis with ascites
2.Serum creatinine >133 μmol/l (1.5 mg/dl)
3.No improvement of serum creatinine (decrease to a level of ≤133 μmol/l) after at least two days of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg body weight per day up to a maximum of 100 g/day
4.Absence of shock
5.No current or recent treatment with nephrotoxic drugs
6.Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/ day, microhematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography
New criteria
M.Farouk HRS
Serum creatinine• loss of muscle mass• reduced dietary protein intake• excerise less than normal• impaired liver function• ethnic• sex
Therefore, false negative diagnosis of HRS is relatively common
M.Farouk HRS
M.Farouk HRS
RIFLE classification(R- renal risk, I- injury, F- failure, L- loss of kidney function, E- end- stage renal disease)
Definitionabrupt (≤48 h) reduction in kidney functionmanifested by an absolute increase in serum creatinine of ≥26 μmol/l (0.3 mg/dl), equivalent to a ≥50% increase in serum creatinine (1.5- fold from baseline)or a urine output of <0.5 ml/kg/h for more than 6h.
The application of these AKI criteria to patients with cirrhosis could lead to the identification of many patients with acute renal dysfunction, normal serum creatinine levels but low GFR.
However, the real usefulness of the AKI criteria must be tested appropriately in the cirrhotic population before recommending these criteria for clinicians to use in clinical practice.
AKI
M.Farouk HRS
Renal Impairment
Hepatorenal syndrome
Othercauses
M.Farouk HRS
Renal failure(serum creatinine >133 mol/L)
Hepatorenal syndrome
Prerenal failure
Fluid losses
Shock
Infection-induced renal failure
Nephrotoxicrenal failure
Nephrotoxic drugs
Abnormal renalultrasonography
His
tory
and
phys
ical
exa
min
ation
Bloo
d an
d ur
ine
chem
istr
ies
Rena
l ul
tras
onog
raph
yParenchymal renal disease
Signs of infection
Persistence of renal failure after
resolution of infection
Proteinuria and/orhaematuria
Acute tubular necrosis“urinary IL-18 (interleukin -18),
NGAL(neutrophil gelatinase associated lipocalin)”
M.Farouk HRS
M.Farouk HRS
Don’t miss the possibility of occurance ofthese major conditions that is
associated with acute renal failurein patients with cirrhosis
•Pancreatitis
•Decreased effective intravascular volume congestive heart failure or other causes of myocardial failure
•Anaphylaxis
•Renal artery or renal vein occlusion by thrombosis; atheroembolism
•Effect of increased intra abdominal pressure on renal perfusion and renal function???
Incidence A multicenter retrospective study
423 patients with cirrhosis and ARFATN (35%)Prerenal failure (32%)HRS (26.6%) Type1 20% & Type2 6.6%
M.Farouk HRS
M.Farouk HRS
1. Doppler ultrasound Early detection of renal vasoconstriction
2. dilutional hyponatremia
3. low urinary sodium
4. reduced plasma osmolality
5. low arterial BP
6. high plasma renin activity
Olivera-Martinez et al., 2012
suggested that:early treatmen might increase survival
In type 1 HRS, a precipitating event is identified in 70 to 100% of patients with HRS, and more than one event can occur in a single patient.
Identifiable precipitating factors include:Bacterial infectionsLarge-volume paracentesis without albumin infusionGastrointestinal bleedingAcute alcoholic hepatitis
•large-volume paracentesis without albumin expansion precipitates type 1 HRS in 15%
•25% of patients who present with acute alcoholic hepatitis eventually develop HRS
•Intravascular volume depletion by overdose diuretic use or lactulose induced diarrhea have been considered triggering factors for HRS; however, evidence to support this is lacking.
M.Farouk HRS
Early identification of a precipitating event of HRS is clinically important because it is frequently preventable or treatable with specific medical therapy.
(Munoz SJ, 2008)
In type 2 HRS and in some patients with type 1 HRS,no precipitating factor can be identified.
M.Farouk HRS
M.Farouk HRS
Treatment
M.Farouk HRS
General Measures
Once diagnosed, treatment should be started early in order to prevent the progression of renal failure.
An excessive administration of fluids should be avoided to prevent fluid overload and development/progression of dilutional hyponatremia.
Potassium-sparing diuretics should not be given because of the risk of severe hyperkalemia.
Careful Monitoring: •urine output,
•and arterial pressure, as well as other standard vital signs.
•Ideally central venous pressure should be monitored to help with the management of fluid balance and prevent volume overload.
•Patients are generally better managed in an intensive care or semi-intensive care unit (Level A1).
M.Farouk HRS
Use of antibiotics•Bacterial infection should be identified early, by blood, urine and ascitic fluid cultures,•and treated with antibiotics•Patients who do not have signs of infection should continue taking prophylactic antibiotics, if previously prescribed•There are no data on the use of antibiotics as empirical treatment for unproven infection in patients presenting with type 1 HRS (Level C1).
Use of beta-blockersThere are no data on whether it is better to stop or continue with beta-blockers in patients with type 1 HRS who are taking these drugs for prophylaxis against variceal bleeding (Level C1).
Use of paracentesisThere are few data on the use of paracentesis in patients with type 1 HRS. Nevertheless, if patients have tense ascites, large-volume paracentesis with albumin is useful in relieving patients’ discomfort (Level B1).
Use of diureticsAll diuretics should be stopped in patients at the initial evaluation and diagnosis of HRS. There are no data to support the use of furosemide in patients with ongoing type 1 HRS. Nevertheless furosemide may be useful to maintain urine output and treat central volume overload if present. Spironolactone is contraindicated because of high risk of life-threatening hyperkalemia (Level A1).
M.Farouk HRS
Pharmacological
RRT
TIPS
Artificial liver support
liver transplantation
M.Farouk HRS
The goal is to reverse renal failure and prolong survival until candidates undergo liver transplantation. Pharmacologic agents can be grouped into two broad categories:
Renal VasodilatorsSystemic Vasoconstrictors
Pharmacological
M.Farouk HRS
+
1 g/kg on day 1 followed by 40 g/dayto improve the efficacy of treatment on circulatory function.
•There is no standardized dose schedule for terlipressin administration because of the lack of dose-finding studies.
•Terlipressin is generally started at a dose of:1 mg/4–6 h and increased to a maximum of2 mg/4–6 h if there is no reduction in serum creatinine of at least 25% compared to the baseline value at day 3 of therapy.
M.Farouk HRS
When stop?
on maximum dose:If no response …………. stop after 4daysIf partial response (<50% reduction in serum creatinine)………… stop after 7daysIf response ………… stop on reversal, with maximum 14 days
M.Farouk HRS
•Response to therapy is generally characterized by:a slowly progressive reduction in serum creatinine (to below 1.5 mg/dl)increase in arterial pressure,increase urine volume,increase serum sodium concentration.
M.Farouk HRS
A serum bilirubin less than 10 mg/dl before treatmentAnd
an increase in mean arterial pressure of >5 mm Hg at day 3 of treatment
are associated with a high probability of response to therapy.
M.Farouk HRS
•Treatment is effective in 40–50% of patients, approximately.
M.Farouk HRS
•The most frequent side effects of treatment:are cardiovascular or ischemic complications
M.Farouk HRS
Treatment with terlipressin is associated with an improved short-term survival.
Treatment with terlipressin has been shown to improve survival in some studies but not in others.
M.Farouk HRS
•Recurrence after withdrawal of therapy is uncommon and retreatment with terlipressin is generally effective.
M.Farouk HRS
+
+
100 mic.g/8 hsubcutaneously,with an increase to200 mic.g/8 h
2.5 to 7.5 mg/8 hwith an increase to12.5 mg/8 h
M.Farouk HRS
Noradrenaline (0.5–3 mg/h) (0.1-0.7mic.g/kg/min) is administered as a continuous infusion.Need further studies to evaluate its efficacy.
M.Farouk HRS
Comparative study : (mean base line serum creatinine 2.4 mg/dl)
83% of the patients responding to noradrenaline were successfully bridged to liver transplantation, with improved survival.No significant ischemic complications occurred in either group. HRS recurred after discontinuation of therapy in about 50% of patients.
But it is still unknown, whether these favorable results apply to patients with severe or advanced HRS (creatinine >4 mg/dL, or severe hepatic decompensation with bilirubin >10 mg/dL, and INR >3).
Noradrenaline+albumin
Terlipressin+albumin
Complete response75%80%
NoradrenalineTerlipressin
cost15 fold
M.Farouk HRS
Comparative study :
Noradrenaline(0.1-0.7μg/kg/min+)
albumin
Midodrine (5-15mg)+octreotide (100-200 μg subcutaneously 3 times)
+albumin
Complete response73%75%
recurrence18%25%
Renal Vasodilators
M.Farouk HRS
Theoretically, supposed to be successfulBut
Unfortunately,None of the studies that used renal vasodilators showed improvement in renal perfusion or GFR
By direct renal vasodilators(dopamine and prostaglandins)
By antagonizing the endogenous effect of renal vasoconstrictors(saralasin, angiotensin-converting enzyme inhibitors, and endothelin antagonist).
Barnardo et al. and Bennett et al.,low-dose dopamine infused for up to 24 himproved cortical blood flow and improved angiographic appearance of renal cortical vasculaturewithout improvement in GFR or urine flow.
M.Farouk HRS
Attempts to use dopamine in combination with vasoconstrictors conferred a better success rate, but this could be attributed to vasoconstrictor therapy.
Similarly, the oral prostaglandin-E1 analog misoprostol or intravenous prostaglandin infusion did not induce significant changes in GFR or sodium excretion. Improvement in renal function occurred in one report but could be explained by volume expansion.
The endothelin-A antagonist BQ-123 demonstrated a dose-dependent renal improvement in three treated patients, but there still is controversy over the role of endothelin blockers in HRS because subsequent studies showed a paradoxic vasodilating effect of endothelin in patients with cirrhosis.
Because of adverse effects and lack of benefit, the use of renal vasodilators in HRS largely has been abandoned
M.Farouk HRS
M.Farouk HRS
There is no line of therapy prevent deathAll therapies for all diseases just prolong survival
Don’t worryWe still have more therapeutic lines
improve renal function in type 1 HRS, but more studies are needed.
improve renal function and control ascites in patients with type 2 HRS.However, TIPS has not been compared with standard medical therapy in type2 patients.
31 patients :•type 1 and type 2 HRS•not candidates for liver transplantation
After TIPS, survival was:3 months ………… 81%6 months ………… 71%12 months ……..… 48%18 months ……..… 35%
7 dialysis-dependent patients …………. 4 discontinued dialysis Moreover, liver transplantation was performed in two patients 7 mo and 2 yr after TIPS, when the medical condition that precluded transplantation has abated.
Transjugular intrahepatic portosystemic shunts
M.Farouk HRS
unanswered observations
First, the clinical and biochemical parameters, although improved, still do not normalize after TIPS, suggesting that TIPS does not correct all of the underlying mechanisms of HRS.
Second, the maximum renal recovery is delayed to 2 to 4 wk after TIPS insertion, and the renal capacity to excrete sodium still is impaired. The cause of this delay and the inability to normalize salt excretion are not clear.
Third, patients with advanced cirrhosis are at risk for worsening liver failure and/or hepatic encephalopathy and are not candidates for TIPS.
Fourth, TIPS has the potential for worsening the existing hyperdynamic circulation or precipitating an underlying acute heart failure; therefore, careful attention to the cardiac status is required.
M.Farouk HRS
14 patients:•cirrhosis and type 1 HRS•oral midodrine and intravenous octreotide with albumin infusion•followed by TIPS insertion in selected patients with preserved liver function (5 patients)
The exciting finding was:persistent improvement in serum creatinine, RPF, GFR, and natriuresis after TIPS insertion, reduction in plasma renin and aldosterone levels 1 mo after TIPS.
All five patients who received combined therapy:were alive 6 to 30 mo after TIPS,with only one patient requiring liver transplantation 13 mo afterward.
patients who responded to vasoconstrictors and did not receive TIPS:either died (three patients) or required a liver transplant (two patients).
M.Farouk HRS
There is a group of patients whom TIPS insertion might prolong survival enough either:to receive a liver transplant or,if they are not candidates, to stay off dialysis
(Wadei et al., 2006)
Combination therapy may preclude the need for future liver transplantation and improve survival compared with vasoconstrictor therapy alone
(Wadei et al., 2006)
TIPS is currently considered an experimental therapy for HRS,that can be considered in a Childs-Pugh class A or B patient,who meets the criteria for TIPS insertion (i.e, serum bilirubin <5 mg/dL, INR <2, and Childs-Pugh score <12),and who fails to respond to vasoconstrictor therapy and plasma volume expansion
(Munoz SJ, Med Clin N Am 92 (2008) 813–837)
TIPS is a valuable option in patients with severe Acute alcoholic hepatitis complicated by HRS and are waiting for liver transplantation.
(Testino et al., 2012)
M.Farouk HRS
Renal replacement therapy
M.Farouk HRS
Precautions that should be taken in consideration: Dose of anticoagulants Dose of Sodium citrate that is metabolized by the liver and the body clearance of this compound has been shown to be significantly reduced in critically ill cirrhotic patients. Monitor serum ionized calcium level and blood pH.
Both hemodialysis or continuous venous hemofiltration, have been used to treat patients with type 1 HRS.
However, published information is very scant.
immediate treatment with renal replacement therapy:severe hyperkalemia,metabolic acidosis,and volume overload
Peritoneal dialysis may be better tolerated by cirrhotic patients than hemodialysis.•enables removal of the ascites fluid•does not expose patients to anticoagulants.
Renal replacement therapy
M.Farouk HRS
Renal replacement therapy may be useful in patients who do not respond to vasoconstrictor therapy, and who fulfill criteria for renal support.
(MARS) the molecular adsorbents recirculating systemPrometheus
may have beneficial effects in patients with type 1 HRS.
more data are needed.
With more encouraging data, this may become a new therapeutic tool in treatment of HRS, serving as a possible bridge to transplantation.
Artificial liver support systems
M.Farouk HRS
In patients with cirrhosis, refractory ascites and type 1 HRS not responding to vasoconstrictor treatment:MARS is ineffective in improving systemic haemodynamics and renal function despite reduction in NO levels.
(Wong et al.,2010)
Liver transplantation is the treatment of choice for both type 1 and type 2 HRS.
in type 1 HRS 3year Survival rates: 65%.
The lower survival rate compared to patients with cirrhosis without HRS:is due to the fact that renal failure is a major predictor of poor outcome after transplantation.
Moreover, patients with type 1 HRS have a high mortality whilst on the waiting list and ideally should be given priority for transplantation.
patients who have been under prolonged renal support therapy (8-12 weeks):Need combined liver–kidney transplantation
Treatment of HRS before transplantation (i.e., with vasoconstrictors) may improve outcome after transplantation.
The improvement in serum creatinine and MELD score after treatment:should not change the decision to perform liver transplantation since the prognosis after recovering from type 1 HRS is still poor.
Liver Transplantation
M.Farouk HRS
M.Farouk HRS
Early identification of a precipitating event of HRS is clinically important because it is frequently preventable or treatable with specific medical therapy.
(Munoz SJ, 2008)
Patients who present with SBP should be treated with intravenous albumin since this has been shown to decrease the incidence of HRS and improve survival (Level A1).
There are some data to suggest thattreatment with pentoxifylline decreases the incidence of HRS in patients with severe alcoholic hepatitis and advanced cirrhosis &treatment with norfloxacin decreases the incidence of HRS in advanced cirrhosis.But further studies are needed (Level B2).
M.Farouk HRS
Prevention of HRS
M.Farouk HRS
Research pointsFor our department
Role of RIFLE staging system for AKI in cirrhotic patients in diagnosis of hepatorenal syndrome especially in cases with normal creatinin values.
M.Farouk HRS
Repeated measurement of serum creatinine over time, particularly in hospitalized patients, is helpful in the early identification of HRS (Level B1).
Research pointsFor our department
Use of beta-blockers: There are no data on whether it is better to stop or continue with beta-blockers in patients with type 1 HRS who are taking these drugs for prophylaxis against variceal bleeding (Level C1).
Use of paracentesis: There are few data on the use of paracentesis in patients with type 1 HRS. Nevertheless, if patients have tense ascites, large-volume paracentesis with albumin is useful in relieving patients’ discomfort (Level B1).
M.Farouk HRS
Research pointsFor our department
There is very limited information with respect to the use of norepinephrine or midodrine plus octreotide, both in association with albumin in patients with type 1 HRS (Level B1).
There are no data on the use of antibiotics as empirical treatment for unproven infection in patients presenting with type 1 HRS (Level C1).
M.Farouk HRS
Research pointsFor our department
TIPS: more studies are needed in type 1 HRS and there is no comaparative studies with standard medical therapy in type 2 HRS.
There are insufficient data on the impact of Terlipressin plus albumin on clinical outcomes in patients with type 2 HRS (Level B1).
M.Farouk HRS
Research pointsFor our department
M.Farouk HRS
There are very limited data on artificial liver support systems, and further studies are needed before its use in clinical practice can be recommended (Level B1).
Research pointsFor our department
M.Farouk HRS
Role of renal biopsy to help plan the further management, including the potential need for combined liver and kidney transplantation.
"إذا وعظت فأوجز, فإنكثرة الكالم ينسي بعضه
"O بعضًاأبو بكر الصديق رضي الله عنه
M.Farouk HRS
TaKeHoMeMeSsAgEs
We must identify precipitating factors and prevent it, and if occurred it must be treated early and appropriately
We have to predict occurance of HRS and treat it early
Put in consideration overestimation (other causes of renal imparement difficult to be differentiated from HRS) and underestimation of HRS (patients with renal impairment despite S.creatinine less than 1.5mg/dl and urine out put that seems to be within normal)
M.Farouk HRS
TaKeHoMeMeSsAgEs
the first line therapeutic agent for type 1 HRS is?a.Midodrine 2.5 to 7.5 mg/8 h and octreotide 100 mic.g/8 h subcutaneously, with an increase to 12.5 mg/8 h and 200 mic.g/8b.Terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin
M.Farouk HRS
TaKeHoMeMeSsAgEs
Recurrence of type 1 HRS after discontinuation of terlipressin therapy is relatively uncommon?(Level A1).a.Treatment with terlipressin should be repeated and is frequently successful.b. Don’t try to repeat terlipressin as it will have no role then.
Contraindications to terlipressin therapy include ischemic cardiovascular diseases.Patients on terlipressin should be carefully monitored for development of cardiac arrhythmias or signs of splanchnic or digital ischemia, and fluid overload, and treatment modified or stopped accordingly.
M.Farouk HRS
TaKeHoMeMeSsAgEs
Terlipressin plus albumin is effective in 60–70% of patients with type 2 HRS. There are insufficient data on the impact of this treatment on clinical outcomes (Level B1).
Liver transplantation is the best treatment for both type 1 and type 2 HRS. HRS should be treated before liver transplantation, since this may improve post-liver transplant outcome (Level A1).
M.Farouk HRS
M.Farouk HRS
SELF RESPECT