Renal Support in Hepatic Renal Support in Hepatic PatientPatient

By Mohammed DabbourBy Mohammed Dabbour Lecturer of Anesthesia

Ain shams University

OutlineOutline IntroductionIntroduction DefinitionDefinition EpidemiologyEpidemiology PathophysiologyPathophysiology Precipitating factorsPrecipitating factors DiagnosisDiagnosis Management (Prevention and Management (Prevention and

treatment)treatment) ConclusionConclusion

IntroductionIntroduction Renal dysfunction is a common and serious Renal dysfunction is a common and serious

problem in patients with advanced liver problem in patients with advanced liver disease. In particular, alterations in renal disease. In particular, alterations in renal physiology in acute liver failure or cirrhosis physiology in acute liver failure or cirrhosis with ascites can predispose patients to a with ascites can predispose patients to a specific functional form of renal failure specific functional form of renal failure known as hepatorenal syndromeknown as hepatorenal syndrome

The accurate assessment of the kidney The accurate assessment of the kidney function and injury is currently affected by function and injury is currently affected by the reliance on the measured the reliance on the measured concentration of serum creatinine,which is concentration of serum creatinine,which is significantly affected by the degree of significantly affected by the degree of cirrhosis, hyperbilirubinemia and the cirrhosis, hyperbilirubinemia and the nutritional state of the patient.nutritional state of the patient.

EpidemiologyEpidemiology

The predictive factors for the The predictive factors for the development of HRS include:development of HRS include:

- a low serum sodium- a low serum sodium

- high plasma rennin- high plasma rennin

- absence of hepatomegaly- absence of hepatomegaly

Co-existing liver and Co-existing liver and kidney diseasekidney disease

■■ Chronic liver disease and primary liver cancerChronic liver disease and primary liver cancer

■■ Obesity and metabolic syndrome are also Obesity and metabolic syndrome are also strongly associated with the development of strongly associated with the development of hypertension and diabeteshypertension and diabetes

■■ Hepatitis C has long been associated with Hepatitis C has long been associated with several glomerulopathiesseveral glomerulopathies

Viral RNA, proteins and particles have been isolated from Viral RNA, proteins and particles have been isolated from kidney biopsy specimen, hepatitis C infection has been kidney biopsy specimen, hepatitis C infection has been reported to be associated with focal segmental reported to be associated with focal segmental glomerulosclerosis. Hepatitis C also has been associated with glomerulosclerosis. Hepatitis C also has been associated with an increased risk of albuminuria, progression of diabetic an increased risk of albuminuria, progression of diabetic nephropathy and progression of kidney disease.nephropathy and progression of kidney disease.

■■ Hepatitis B virus (HBV) is Hepatitis B virus (HBV) is associated with a number of renal associated with a number of renal disease, including polyarteritis disease, including polyarteritis nodosa, membranous and nodosa, membranous and membranoproliferative membranoproliferative glomerulonephritisglomerulonephritis

■ ■ Autosomal-dominant polycystic Autosomal-dominant polycystic kidney is associated with polycystic kidney is associated with polycystic liver disease in up to 75-90% of liver disease in up to 75-90% of cases cases

■■ Familial amyloidosis is an Familial amyloidosis is an autosomal dominant diseaseautosomal dominant disease

Renal diseases associated with Renal diseases associated with major types of liver diseasemajor types of liver disease

Hepatitis BMembranous glomerulonephritis (GN), membranoproliferative GN, IgA nephropathy, focal segmental glomerulosclerosis

Hepatitis CMembranoproliferative GN, membranous GN, cryoglobulinemia, fibrillary GN, IgA nephropathy, tubulointerstitial nephritis

Alcoholic liver diseaseIgA nephropathy

Obstructive jaundicePrerenal azotemia/acute tubular necrosis from hypovolemia, decreased cardiac output, sepsis; acute tubular necrosis

Primary biliary cirrhosis

Membranous GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, antiglomerular basement membrane disease, renal tubular acidosis, tubulointerstitial nephritis

Primary sclerosing cholangitis

Membranous GN, membranoproliferative GN, antineutrophil cytoplasmic autoantibody-positive vasculitis

Wilson’s diseaseRenal tubular acidosis (Type 1) secondary to copper deposition

Alpha-1 antitrypsin deficiency

Membranoproliferative GN, antiglomerular basement membrane disease

Systemic diseases Systemic diseases involving both liver and involving both liver and

kidneykidneyDrug toxicityAcetaminophen, ASA

Granulomatous diseasesSarcoidosis

Infectious diseasesMalaria

Infiltrative diseasesAmyloidosis

InflammatoryLupus

Non alcoholic fatty liver disease

Pre-eclapmsia/HELLP Hmeloysis, elevated liver enzymes, low platelets

Polycystic kidney/liver diseaseAutosomal dominant

Sickle cell disease

Shock statesCongestive heart failure, sepsis, hypovolemia

Serum creatinine concentration Serum creatinine concentration for the assessment of kidney for the assessment of kidney

function in chronic liver diseasefunction in chronic liver disease Kidney function is evaluated by assessing the GFR which can Kidney function is evaluated by assessing the GFR which can

be determined by measuring the volume of plasma that can be determined by measuring the volume of plasma that can be cleared of a given substance over a timed unit of timebe cleared of a given substance over a timed unit of time

GFR has relied on the measurement of the concentration of GFR has relied on the measurement of the concentration of serum creatinineserum creatinine, which is associated with many problems:, which is associated with many problems:

- specific, but not sensitive- specific, but not sensitive

- measurement is affected by gender, age, ethnicity, - measurement is affected by gender, age, ethnicity, nutritional state, protein intake and importantly, nutritional state, protein intake and importantly, liver disease liver disease

In chronic liver disease, the reduction in serum creatinine is In chronic liver disease, the reduction in serum creatinine is due to a 50% decrease in hepatic production of creatinine due to a 50% decrease in hepatic production of creatinine and increase in the volume distributionand increase in the volume distribution

Acute Kidney Injury Network Acute Kidney Injury Network Criteria for staging Acute Criteria for staging Acute

Kidney InjuryKidney Injury

In 2005, the Acute Kidney Injury In 2005, the Acute Kidney Injury Network (AKIN) developed the Network (AKIN) developed the RIFLERIFLE (Risk, Injury, Failure, Loss, End stage (Risk, Injury, Failure, Loss, End stage renal disease)renal disease) criteria criteria

Acute kidney injury network(AKIN)acute kidney injury staging criteria

Acute Kidney Injury Acute Kidney Injury PathogenesisPathogenesis

AA. . Isolated ischemic injury Isolated ischemic injury →→ Inflammatory Inflammatory response response →→ Leucocyte release & tubular Leucocyte release & tubular damage damage →→ impaired Na reabsorption impaired Na reabsorption →→ polymerization of Tamm-Horsfall proteins polymerization of Tamm-Horsfall proteins →→ gel-like substance formation gel-like substance formation →→ tubular tubular occlusion occlusion →→ increased backpressure & leaking increased backpressure & leaking

BB. . Endothelial injury Endothelial injury →→ affects afferent affects afferent arteriolar tonicity arteriolar tonicity →→ clotting cascade clotting cascade activation & endothelin release activation & endothelin release →→ VC VC →→ compromising the microcirculationcompromising the microcirculation

Bacterial

infection

Large volume

paracentesis

GIt bleedingAcute

alcoholic hepatitis

Renal vasoconstriction

Cardiac dysfunction

((septic or cirrhotic

Worsening hyperdynamic

circulation

Renal Vasoconstrictor ↑ Renal Vasodilator ↓

Biomarkers of AKIBiomarkers of AKI Traditional markersTraditional markers::- Serum creatinineSerum creatinine- Serum ureaSerum urea- Urine markerUrine markerss- Fractional excretion of sodiumFractional excretion of sodium- Urine casts on microscopyUrine casts on microscopy

Novel kidney biomarkersNovel kidney biomarkers::Two serum Two serum and three urine biomarkersand three urine biomarkers

- Serum neutrophil gelatinase Lipocalin (sNGAL) Serum neutrophil gelatinase Lipocalin (sNGAL) - Cystatin CCystatin C- Urinary Kidney Injury Molecule (KIM-1)Urinary Kidney Injury Molecule (KIM-1)- Interleukin-18 (IL-18)Interleukin-18 (IL-18)- NGAL (uNGAL)NGAL (uNGAL)

`̀Summary of studies evaluating the role of novel blood and urine kidney injury biomarkers

Precipitating FactorsPrecipitating Factors

Spontaneous bacterial Spontaneous bacterial peritonitisperitonitis

Gastrointestinal bleedingGastrointestinal bleedingAggressive paracentesisAggressive paracentesisDrugsDrugsOthersOthers

Spontaneous Bacterial Spontaneous Bacterial PeritonitisPeritonitis

Renal impairment is related to further Renal impairment is related to further deterioration of systemic deterioration of systemic hemodynamics, mostly by endotoxins hemodynamics, mostly by endotoxins and various cytokines induced in SBP, and various cytokines induced in SBP, causing further vasodilatationcausing further vasodilatation

Gastrointestinal bleedingGastrointestinal bleeding Acute gastrointestinal bleeding leads Acute gastrointestinal bleeding leads

to acute blood volume contraction, to acute blood volume contraction, with decreased renal perfusionwith decreased renal perfusion

Aggressive paracentesisAggressive paracentesis It reduces the effective arterial blood volume and It reduces the effective arterial blood volume and

further activates vasoconstrictor systemfurther activates vasoconstrictor system

DrugsDrugs- DiureticsDiuretics- AminoglycosidesAminoglycosides- Nonsteroidal anti-inflammatory drugsNonsteroidal anti-inflammatory drugs- ACE-inhibitorsACE-inhibitors- Angiotensin II antagonistsAngiotensin II antagonists

Others:Others:- Surgery, acute alcoholic hepatitis and cholestasis- Surgery, acute alcoholic hepatitis and cholestasis

Definition of HRSDefinition of HRS

HRS is defined as the development HRS is defined as the development of renal failure in patients with of renal failure in patients with advanced liver failure (acute or advanced liver failure (acute or chronic) in the absence of any chronic) in the absence of any identifiable causes of renal identifiable causes of renal pathologypathology

In 1996, the International Ascites In 1996, the International Ascites Club subdivided HRS into 2 types;Club subdivided HRS into 2 types;

Hepatorenal syndromeHepatorenal syndromeType IType I

-■■ characterized by a characterized by a rapid decline in renal rapid decline in renal functionfunction

-■■ defined as a doubling of defined as a doubling of serum creatinine to a serum creatinine to a level > 2.5 mg/dL or a level > 2.5 mg/dL or a halving of the creatinine halving of the creatinine clearance to < 20 clearance to < 20 mL/min within 2 weeksmL/min within 2 weeks

-■■ clinical presentation is clinical presentation is that of acute renal failurethat of acute renal failure

Type IIType II

■■ renal function renal function deteriorates more slowlydeteriorates more slowly

■■ serum creatinine serum creatinine increases to > 1.5 mg/dL increases to > 1.5 mg/dL or a creatinine clearance or a creatinine clearance of < 40 mL/minof < 40 mL/min . .

■ ■The clinical presentation The clinical presentation is that of stable renal is that of stable renal failure in a patient with failure in a patient with refractory ascitesrefractory ascites

Diagnosis of HRSDiagnosis of HRS

Some patients with Some patients with primary liver primary liver disease disease are at higher risk for are at higher risk for developing certain forms of kidney developing certain forms of kidney disease while some disease while some systemic systemic processes processes can affect both liver and can affect both liver and kidneykidney

Major criteria Major criteria should be fulfilled to should be fulfilled to confirm diagnosisconfirm diagnosis

Hepatorenal syndrome: Hepatorenal syndrome: Diagnostic criteriaDiagnostic criteria

Major criteria Major criteria (all must be (all must be present)present)

Chronic or acute liver disease with advanced hepatic Chronic or acute liver disease with advanced hepatic failure and portal hypertensionfailure and portal hypertension

Low GFR as indicated by a 24-hr creatinine clearance of Low GFR as indicated by a 24-hr creatinine clearance of < 40 mL/min or serum creatinine > 1.5 mg/dL< 40 mL/min or serum creatinine > 1.5 mg/dL

Absence of shock, sepsis, volume depletion, exposure to Absence of shock, sepsis, volume depletion, exposure to nephrotoxinsnephrotoxins

No sustained improvement in renal function (to No sustained improvement in renal function (to creatinine > 1.5 mg/dL or 24-hr CrCl to > 40 mL/min) creatinine > 1.5 mg/dL or 24-hr CrCl to > 40 mL/min) following diuretic withdrawal or plasma volume following diuretic withdrawal or plasma volume expansion with 1.5 L of normal salineexpansion with 1.5 L of normal saline

Proteinuria < 500 mg/dLProteinuria < 500 mg/dL No ultrasonographic findings of obstructive uropathy or No ultrasonographic findings of obstructive uropathy or

parenchymal renal diseaseparenchymal renal disease

Additional criteria Additional criteria (not necessary but would (not necessary but would support diagnosis)support diagnosis)

Urine volume < 500 mL/dayUrine volume < 500 mL/day Urine sodium < 10 mEq/LUrine sodium < 10 mEq/L Urine osmolality greater than plasma Urine osmolality greater than plasma

osmolalityosmolality Urine red blood cells < 50 per high-power Urine red blood cells < 50 per high-power

fieldfield Serum sodium < 130 mEq/LSerum sodium < 130 mEq/L

Work-up for patients with Work-up for patients with suspected HRSsuspected HRS HistoryHistory

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

agentsagents

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

InvestigationsInvestigations Complete blood count, electrolytes, creatinine levelComplete blood count, electrolytes, creatinine level Urine sodium, osmolalityUrine sodium, osmolality Urinalysis for protein, cells, and castsUrinalysis for protein, cells, and casts Renal ultrasoundRenal ultrasound

Assessment of Chronic Assessment of Chronic kidney Disease in kidney Disease in

patients with chronic patients with chronic Liver diseaseLiver disease Timed urine creatinine clearance Timed urine creatinine clearance

performs poor significance performs poor significance overestimating GFR in patients with overestimating GFR in patients with chronic liver diseasechronic liver disease

So why use estimated GFR if it So why use estimated GFR if it

performs so poorly performs so poorly ?????????? Because it is the most cost-effective Because it is the most cost-effective

method of assessing kidney function in method of assessing kidney function in chronic caseschronic cases

Staging criteria for chronic kidney disease

Management of HRSManagement of HRSPrevention & treatmentPrevention & treatment

♣ ♣ PreventionPrevention::- Prophylaxis against bacterial Prophylaxis against bacterial

infectioninfection- Volume expansionVolume expansion- Strict use of diureticsStrict use of diuretics- Avoidance of nephrotoxic agentsAvoidance of nephrotoxic agents

♣ ♣ Treatment:Treatment: Initial management:Initial management:It requires exclusion of reversible or treatable It requires exclusion of reversible or treatable

conditionsconditions Pharmacologic therapyPharmacologic therapy Renal supportRenal support Transjugular Intrahepatic Portosystemic Transjugular Intrahepatic Portosystemic

ShuntShunt Liver transplantationLiver transplantation

Pharmacologic therapyPharmacologic therapy● ● DopamineDopamine Has renal vasodilator effect when given in subpressor doses, but no studies have shown Has renal vasodilator effect when given in subpressor doses, but no studies have shown

convincing benifitconvincing benifit

● ● NoradrenalineNoradrenaline

was used with albumin and frusemide in management of patients with type I HRSwas used with albumin and frusemide in management of patients with type I HRS

● ● Midodrine & OctreotideMidodrine & Octreotide

MidodrineMidodrine is an oral alpha adrenergic agent and sympathomimetic drug is an oral alpha adrenergic agent and sympathomimetic drug

OctreotideOctreotide is a long acting analog of somatostatin is a long acting analog of somatostatin

Combined long term administration of oral midodrine and subcutaneous octreotide lead to improvement Combined long term administration of oral midodrine and subcutaneous octreotide lead to improvement in renal function compared with nonpressor doses of dopaminein renal function compared with nonpressor doses of dopamine

● ● MisoprostolMisoprostol

It is a synthetic analogue of prostaglandin E1, It is a synthetic analogue of prostaglandin E1, acts as a renal vasodilator acts as a renal vasodilator

● ● OrnipressinOrnipressin

It is a nonselective agonist of V1 vasopressin It is a nonselective agonist of V1 vasopressin receptors that causes VC of the splanchnic receptors that causes VC of the splanchnic vasculature, thus increasing systemic pressure vasculature, thus increasing systemic pressure and renal perfusion pressureand renal perfusion pressure

● ● TerlipressinTerlipressin

It is a synthetic analogue of vasopressin with It is a synthetic analogue of vasopressin with VC activityVC activity

. Lowers incidence of ischemic complications. Lowers incidence of ischemic complications

. Longer half life than vasopressin. Longer half life than vasopressin

● ● Endothelin anatgonistsEndothelin anatgonists

Enothelin is a potent endogenous Enothelin is a potent endogenous vasoconstrictor, so renal failure was vasoconstrictor, so renal failure was prevented by an endothelin anatgonist, prevented by an endothelin anatgonist, e.g., e.g., BosentanBosentan

● ● N-acetylcysteineN-acetylcysteine

It is a drug with antioxidant propertiesIt is a drug with antioxidant properties

● ● PentoxifyllinPentoxifyllin It inhibits the tumor necrosis factorIt inhibits the tumor necrosis factor

Renal supportRenal support

Dialysis:Dialysis:

The effectiveness of dialysis has not been provenThe effectiveness of dialysis has not been proven Molecular Adsorbent Recirculating Molecular Adsorbent Recirculating

SystemSystem This system is a modified form of dialysis using This system is a modified form of dialysis using

albumin-containing dialysate that is albumin-containing dialysate that is recirculated and perfused online through recirculated and perfused online through charcoal and anion exchanger columns.charcoal and anion exchanger columns.

It enables the removal of water and albumin It enables the removal of water and albumin bound substancesbound substances

Transjugular Intrahepatic Transjugular Intrahepatic Portosystemic ShuntPortosystemic Shunt

Liver transplantationLiver transplantation Endstage liver and kidney disease Endstage liver and kidney disease

is a recognized indication for is a recognized indication for combined liver-kidney transplantcombined liver-kidney transplant

ConclusionConclusion Chronic liver disease is associated with Chronic liver disease is associated with

primary and secondary kidney diseaseprimary and secondary kidney disease Evaluation of kidney function relies on the Evaluation of kidney function relies on the

measurement of serum creatinine, which is measurement of serum creatinine, which is affected by the degree of liver diseaseaffected by the degree of liver disease

Hepatologists should use exogenous measures Hepatologists should use exogenous measures of kidney functions & biomarkers like cystatin of kidney functions & biomarkers like cystatin CC

Kidney Injury Biomarkers need further Kidney Injury Biomarkers need further evaluation in the chronic liver disease evaluation in the chronic liver disease populationpopulation

Early diagnosis potentially increases the Early diagnosis potentially increases the survival outcomessurvival outcomes

Numerous studies have shown the Numerous studies have shown the benefit of terlipressin with fewer benefit of terlipressin with fewer side effectsside effects

The combination of midodrine and The combination of midodrine and octreotide can be used in absence of octreotide can be used in absence of terlipressinterlipressin

Intravenous albumin should be Intravenous albumin should be considered.considered.

Orthotopic liver transplantation is Orthotopic liver transplantation is the most effective strategy for the the most effective strategy for the treatment of hepatorenal syndrome.treatment of hepatorenal syndrome.