2. Renal Support in Hepatic Patient By Mohammed Dabbour Lecturer of Anesthesia Ain shams University

3. Outline Introduction Introduction Definition Definition Epidemiology Epidemiology Pathophysiology Pathophysiology Precipitating factors Precipitating factors Diagnosis Diagnosis Management (Prevention and treatment) Management (Prevention and treatment) Conclusion Conclusion

4. Introduction Renal dysfunction is a common and serious problem in patients with advanced liver disease. In particular, alterations in renal physiology in acute liver failure or cirrhosis with ascites can predispose patients to a specific functional form of renal failure known as hepatorenal syndrome Renal dysfunction is a common and serious problem in patients with advanced liver disease. In particular, alterations in renal physiology in acute liver failure or cirrhosis with ascites can predispose patients to a specific functional form of renal failure known as hepatorenal syndrome The accurate assessment of the kidney function and injury is currently affected by the reliance on the measured concentration of serum creatinine,which is significantly affected by the degree of cirrhosis, hyperbilirubinemia and the nutritional state of the patient. The accurate assessment of the kidney function and injury is currently affected by the reliance on the measured concentration of serum creatinine,which is significantly affected by the degree of cirrhosis, hyperbilirubinemia and the nutritional state of the patient.

5. Epidemiology The predictive factors for the development of HRS include: The predictive factors for the development of HRS include: - a low serum sodium - a low serum sodium - high plasma rennin - high plasma rennin - absence of hepatomegaly - absence of hepatomegaly

6. Co-existing liver and kidney disease ■ Chronic liver disease and primary liver cancer ■ Obesity and metabolic syndrome are also strongly associated with the development of hypertension and diabetes ■ Hepatitis C has long been associated with several glomerulopathies Viral RNA, proteins and particles have been isolated from kidney biopsy specimen, hepatitis C infection has been reported to be associated with focal segmental glomerulosclerosis. Hepatitis C also has been associated with an increased risk of albuminuria, progression of diabetic nephropathy and progression of kidney disease. Viral RNA, proteins and particles have been isolated from kidney biopsy specimen, hepatitis C infection has been reported to be associated with focal segmental glomerulosclerosis. Hepatitis C also has been associated with an increased risk of albuminuria, progression of diabetic nephropathy and progression of kidney disease.

7. ■ Hepatitis B virus (HBV) is associated with a number of renal disease, including polyarteritis nodosa, membranous and membranoproliferative glomerulonephritis ■ Hepatitis B virus (HBV) is associated with a number of renal disease, including polyarteritis nodosa, membranous and membranoproliferative glomerulonephritis ■ Autosomal-dominant polycystic kidney is associated with polycystic liver disease in up to 75-90% of cases ■ Autosomal-dominant polycystic kidney is associated with polycystic liver disease in up to 75-90% of cases ■ Familial amyloidosis is an autosomal dominant disease ■ Familial amyloidosis is an autosomal dominant disease

8. Renal diseases associated with major types of liver disease Membranous glomerulonephritis (GN), membranoproliferative GN, IgA nephropathy, focal segmental glomerulosclerosis Hepatitis B Membranoproliferative GN, membranous GN, cryoglobulinemia, fibrillary GN, IgA nephropathy, tubulointerstitial nephritis Hepatitis C IgA nephropathy Alcoholic liver disease Prerenal azotemia/acute tubular necrosis from hypovolemia, decreased cardiac output, sepsis; acute tubular necrosis Obstructive jaundice Membranous GN, antineutrophil cytoplasmic autoantibody- positive vasculitis, antiglomerular basement membrane disease, renal tubular acidosis, tubulointerstitial nephritis Primary biliary cirrhosis Membranous GN, membranoproliferative GN, antineutrophil cytoplasmic autoantibody-positive vasculitis Primary sclerosing cholangitis Renal tubular acidosis (Type 1) secondary to copper deposition Wilson’s disease Membranoproliferative GN, antiglomerular basement membrane disease Alpha-1 antitrypsin deficiency

9. Systemic diseases involving both liver and kidney Acetaminophen, ASADrug toxicity SarcoidosisGranulomatous diseases MalariaInfectious diseases AmyloidosisInfiltrative diseases LupusInflammatory Non alcoholic fatty liver disease Pre-eclapmsia/HELLP Hmeloysis, elevated liver enzymes, low platelets Autosomal dominantPolycystic kidney/liver disease Sickle cell disease Congestive heart failure, sepsis, hypovolemiaShock states

10. Serum creatinine concentration for the assessment of kidney function in chronic liver disease Kidney function is evaluated by assessing the GFR which can be determined by measuring the volume of plasma that can be cleared of a given substance over a timed unit of time Kidney function is evaluated by assessing the GFR which can be determined by measuring the volume of plasma that can be cleared of a given substance over a timed unit of time GFR has relied on the measurement of the concentration of serum creatinine, which is associated with many problems: GFR has relied on the measurement of the concentration of serum creatinine, which is associated with many problems: - specific, but not sensitive - specific, but not sensitive - measurement is affected by gender, age, ethnicity, nutritional state, protein intake and importantly, liver disease - measurement is affected by gender, age, ethnicity, nutritional state, protein intake and importantly, liver disease In chronic liver disease, the reduction in serum creatinine is due to a 50% decrease in hepatic production of creatinine and increase in the volume distribution In chronic liver disease, the reduction in serum creatinine is due to a 50% decrease in hepatic production of creatinine and increase in the volume distribution

11. Acute Kidney Injury Network Criteria for staging Acute Kidney Injury In 2005, the Acute Kidney Injury Network (AKIN) developed the RIFLE (Risk, Injury, Failure, Loss, End stage renal disease) criteria In 2005, the Acute Kidney Injury Network (AKIN) developed the RIFLE (Risk, Injury, Failure, Loss, End stage renal disease) criteria

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

13. Acute Kidney Injury Pathogenesis A. Isolated ischemic injury → Inflammatory response → Leucocyte release & tubular damage → impaired Na reabsorption → polymerization of Tamm-Horsfall proteins → gel-like substance formation → tubular occlusion → increased backpressure & leaking B. Endothelial injury → affects afferent arteriolar tonicity → clotting cascade activation & endothelin release → VC → compromising the microcirculation

14. Bacterial infection Large volume paracentesis GIt bleeding Acute alcoholic hepatitis Renal vasoconstriction Cardiac dysfunction ((septic or cirrhotic Worsening hyperdynamic circulation Renal Vasoconstrictor ↑ Renal Vasodilator ↓

15. Biomarkers of AKI Traditional markers: Traditional markers: - Serum creatinine - Serum urea - Urine markers - Fractional excretion of sodium - Urine casts on microscopy Novel kidney biomarkers :Two serum and three urine biomarkers Novel kidney biomarkers :Two serum and three urine biomarkers - Serum neutrophil gelatinase Lipocalin (sNGAL) - Cystatin C - Urinary Kidney Injury Molecule (KIM-1) - Interleukin-18 (IL-18) - NGAL (uNGAL)

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

17. Precipitating Factors Spontaneous bacterial peritonitis Spontaneous bacterial peritonitis Gastrointestinal bleeding Gastrointestinal bleeding Aggressive paracentesis Aggressive paracentesis Drugs Drugs Others Others

18. Spontaneous Bacterial Peritonitis Renal impairment is related to further deterioration of systemic hemodynamics, mostly by endotoxins and various cytokines induced in SBP, causing further vasodilatation Renal impairment is related to further deterioration of systemic hemodynamics, mostly by endotoxins and various cytokines induced in SBP, causing further vasodilatation Gastrointestinal bleeding Gastrointestinal bleeding Acute gastrointestinal bleeding leads to acute blood volume contraction, with decreased renal perfusion Acute gastrointestinal bleeding leads to acute blood volume contraction, with decreased renal perfusion

19. Aggressive paracentesis Aggressive paracentesis It reduces the effective arterial blood volume and further activates vasoconstrictor system It reduces the effective arterial blood volume and further activates vasoconstrictor system Drugs Drugs - Diuretics - Aminoglycosides - Nonsteroidal anti-inflammatory drugs - ACE-inhibitors - Angiotensin II antagonists Others: - Surgery, acute alcoholic hepatitis and cholestasis

20. Definition of HRS HRS is defined as the development of renal failure in patients with advanced liver failure (acute or chronic) in the absence of any identifiable causes of renal pathology HRS is defined as the development of renal failure in patients with advanced liver failure (acute or chronic) in the absence of any identifiable causes of renal pathology In 1996, the International Ascites Club subdivided HRS into 2 types; In 1996, the International Ascites Club subdivided HRS into 2 types;

21. Hepatorenal syndrome Type I - ■ characterized by a rapid decline in renal function - ■ defined as a doubling of serum creatinine to a level > 2.5 mg/dL or a halving of the creatinine clearance to < 20 mL/min within 2 weeks - ■ clinical presentation is that of acute renal failure Type II ■ renal function deteriorates more slowly ■ serum creatinine increases to > 1.5 mg/dL or a creatinine clearance of < 40 mL/min. ■ The clinical presentation is that of stable renal failure in a patient with refractory ascites

22. Diagnosis of HRS Some patients with primary liver disease are at higher risk for developing certain forms of kidney disease while some systemic processes can affect both liver and kidney Some patients with primary liver disease are at higher risk for developing certain forms of kidney disease while some systemic processes can affect both liver and kidney Major criteria should be fulfilled to confirm diagnosis Major criteria should be fulfilled to confirm diagnosis

23. Hepatorenal syndrome: Diagnostic criteria Major criteria (all must be present) Major criteria (all must be present) Chronic or acute liver disease with advanced hepatic failure and portal hypertension Chronic or acute liver disease with advanced hepatic failure and portal hypertension Low GFR as indicated by a 24-hr creatinine clearance of 1.5 mg/dL Low GFR as indicated by a 24-hr creatinine clearance of 1.5 mg/dL Absence of shock, sepsis, volume depletion, exposure to nephrotoxins Absence of shock, sepsis, volume depletion, exposure to nephrotoxins No sustained improvement in renal function (to creatinine > 1.5 mg/dL or 24-hr CrCl to > 40 mL/min) following diuretic withdrawal or plasma volume expansion with 1.5 L of normal saline No sustained improvement in renal function (to creatinine > 1.5 mg/dL or 24-hr CrCl to > 40 mL/min) following diuretic withdrawal or plasma volume expansion with 1.5 L of normal saline Proteinuria < 500 mg/dL Proteinuria < 500 mg/dL No ultrasonographic findings of obstructive uropathy or parenchymal renal disease No ultrasonographic findings of obstructive uropathy or parenchymal renal disease

24. Additional criteria (not necessary but would support diagnosis) Additional criteria (not necessary but would support diagnosis)  Urine volume < 500 mL/day  Urine sodium < 10 mEq/L  Urine osmolality greater than plasma osmolality  Urine red blood cells < 50 per high-power field  Serum sodium < 130 mEq/L

25. Work-up for patients with suspected HRS History 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 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 Investigations Complete blood count, electrolytes, creatinine level Complete blood count, electrolytes, creatinine level Urine sodium, osmolality Urine sodium, osmolality Urinalysis for protein, cells, and casts Urinalysis for protein, cells, and casts Renal ultrasound Renal ultrasound

26. Assessment of Chronic kidney Disease in patients with chronic Liver disease Timed urine creatinine clearance performs poor significance overestimating GFR in patients with chronic liver disease Timed urine creatinine clearance performs poor significance overestimating GFR in patients with chronic liver disease So why use estimated GFR if it performs so poorly ????? So why use estimated GFR if it performs so poorly ????? Because it is the most cost-effective method of assessing kidney function in chronic cases Because it is the most cost-effective method of assessing kidney function in chronic cases

27. Staging criteria for chronic kidney disease

28. Management of HRS Prevention & treatment ♣ Prevention: - Prophylaxis against bacterial infection - Volume expansion - Strict use of diuretics - Avoidance of nephrotoxic agents

29. ♣ Treatment: Initial management: Initial management: It requires exclusion of reversible or treatable conditions Pharmacologic therapy Pharmacologic therapy Renal support Renal support Transjugular Intrahepatic Portosystemic Shunt Transjugular Intrahepatic Portosystemic Shunt Liver transplantation Liver transplantation

30. Pharmacologic therapy ● Dopamine Has renal vasodilator effect when given in subpressor doses, but no studies have shown convincing benifit Has renal vasodilator effect when given in subpressor doses, but no studies have shown convincing benifit ● Noradrenaline was used with albumin and frusemide in management of patients with type I HRS was used with albumin and frusemide in management of patients with type I HRS ● Midodrine & Octreotide Midodrine is an oral alpha adrenergic agent and sympathomimetic drug Midodrine is an oral alpha adrenergic agent and sympathomimetic drug Octreotide is a long acting analog of somatostatin Octreotide is a long acting analog of somatostatin Combined long term administration of oral midodrine and subcutaneous octreotide lead to improvement in renal function compared with nonpressor doses of dopamine Combined long term administration of oral midodrine and subcutaneous octreotide lead to improvement in renal function compared with nonpressor doses of dopamine

31. ● Misoprostol It is a synthetic analogue of prostaglandin E1, acts as a renal vasodilator It is a synthetic analogue of prostaglandin E1, acts as a renal vasodilator ● Ornipressin It is a nonselective agonist of V1 vasopressin receptors that causes VC of the splanchnic vasculature, thus increasing systemic pressure and renal perfusion pressure It is a nonselective agonist of V1 vasopressin receptors that causes VC of the splanchnic vasculature, thus increasing systemic pressure and renal perfusion pressure ● Terlipressin It is a synthetic analogue of vasopressin with VC activity It is a synthetic analogue of vasopressin with VC activity. Lowers incidence of ischemic complications. Lowers incidence of ischemic complications. Longer half life than vasopressin. Longer half life than vasopressin

32. ● Endothelin anatgonists Enothelin is a potent endogenous vasoconstrictor, so renal failure was prevented by an endothelin anatgonist, e.g., Bosentan Enothelin is a potent endogenous vasoconstrictor, so renal failure was prevented by an endothelin anatgonist, e.g., Bosentan ● N-acetylcysteine It is a drug with antioxidant properties It is a drug with antioxidant properties ● Pentoxifyllin It inhibits the tumor necrosis factor It inhibits the tumor necrosis factor

33. Renal support Dialysis: Dialysis: The effectiveness of dialysis has not been proven The effectiveness of dialysis has not been proven Molecular Adsorbent Recirculating System Molecular Adsorbent Recirculating System This system is a modified form of dialysis using albumin-containing dialysate that is recirculated and perfused online through charcoal and anion exchanger columns. This system is a modified form of dialysis using albumin-containing dialysate that is recirculated and perfused online through charcoal and anion exchanger columns. It enables the removal of water and albumin bound substances It enables the removal of water and albumin bound substances

34. Transjugular Intrahepatic Portosystemic Shunt Transjugular Intrahepatic Portosystemic Shunt Liver transplantation Liver transplantation Endstage liver and kidney disease is a recognized indication for combined liver-kidney transplant Endstage liver and kidney disease is a recognized indication for combined liver-kidney transplant

35. Conclusion Chronic liver disease is associated with primary and secondary kidney disease Chronic liver disease is associated with primary and secondary kidney disease Evaluation of kidney function relies on the measurement of serum creatinine, which is affected by the degree of liver disease Evaluation of kidney function relies on the measurement of serum creatinine, which is affected by the degree of liver disease Hepatologists should use exogenous measures of kidney functions & biomarkers like cystatin C Hepatologists should use exogenous measures of kidney functions & biomarkers like cystatin C Kidney Injury Biomarkers need further evaluation in the chronic liver disease population Kidney Injury Biomarkers need further evaluation in the chronic liver disease population Early diagnosis potentially increases the survival outcomes Early diagnosis potentially increases the survival outcomes

36. Numerous studies have shown the benefit of terlipressin with fewer side effects Numerous studies have shown the benefit of terlipressin with fewer side effects The combination of midodrine and octreotide can be used in absence of terlipressin The combination of midodrine and octreotide can be used in absence of terlipressin Intravenous albumin should be considered. Intravenous albumin should be considered. Orthotopic liver transplantation is the most effective strategy for the treatment of hepatorenal syndrome. Orthotopic liver transplantation is the most effective strategy for the treatment of hepatorenal syndrome.