Case Presentation• 56 Yr old AA Female with PMH of cirrhosis• C/o Diarrhea since April 2011.• Abdominal distention• Abdominal pain for 1 day, dull, aching, diffuse, 4/10 in intensity• Associated with Nausea and Vomiting• Hemetemesis , day of presentation.• Denies fever, Chills
• Family history- HTN in mother• Social history: Denies alcohol or drug abuse.• ROS: b/l lower Extremity edema. UGIB, Blood Transfusion.• Paracentesis- September 15, 2011, 4.6 L removed; August 1, 2011-6 L
Physical Exam• Temp: 98.7 Pulse: 97 RR:20 Pulse Ox: 98% on RA, BP: 134/70• HEENT: Scleral Icterus, Conjunctival Pallor• RS: Clear to auscultation, no respiratory distress• CVS: Normal S1/S2• Abdomen: Distended, Tense, no tenderness on palpation• Extremities: 3+ pitting edema B/l lower Extremities.
Diagnostic Tests and Studies• WBC: 5.2, Hb: 7.5<- 8.6, Plt: 236• Na:137, K+:3.4, BUN: 46, Creatinine: 8.0<-2.6• Albumin: 2.5, T.bil: 1.5, Alk Phos: 155, U.Na+-10, U.creat-520, FENa-0.1%• AST: 195 ALT: 65 Complement levels - normal• Colonoscopy(9/6/11): normal• CT scan abdomen(7/11/11)-hepatic Cirrhosis, right renal calculi, Findings of portal hypertension, including moderate abdominopelvic ascites and splenomegaly,Mild right renal atrophy and compensatory hypertrophy of the left kidney• USG abdomen: enlarged liver, portal hypertension, moderate ascites, normal sized kidneys.
Hospital Course• Admitted to ICU for UGIB and received blood transfusion.• Parcentesis done: no organisms.• Underwent EGD, showed esophageal varices and got banding for same.• During stay in ICU had very poor UO, 8-10 ml/hr• Medications in hospital: Protonix Gtt, Ceftriaxone.• Her creatinine elevated at 7.9, GU c/s for foley catheter, after foley placed Cr.8.1, Uo-20 ml/hr even after receiving multiple fluid boluses.• Patient was stable hemodynamically and her creatinine improved to 7.7, the patient was advised to be transferred to UPEN for further evaluation and possible liver transplant.
• But she was denied for liver transplant secondary to high BMI.• She was transferred to floor and her creatinine was not improving and she was C/o shortness of breath and underwent paracentesis and felt better.• She was also started on midodrine and octreotide without much improvement• She developed uremic symptoms and thus started on dialysis.
HepatoRenal Syndrome (International Ascites Club Definition)• HepatoRenal syndrome is the clinical condition that develops in patients with Chronic liver disease and advanced hepatic failure and portal HTN characterized by impaired renal function and marked abnormalities in arterial circulation and activity of endogenous vasoactive systems. In the kidney, there is marked renal vasoconstriction that results in low GFR. There is also vasoconstriction in other vascular territories such as muscle, spleen and brain. In the splanchnic circulation, there is an intense arteriolar vasodilatation that results in reduction of total systemic vascular resistance and arterial hypotension. A similar syndrome can also develop in the setting of acute liver failure.
HepatoRenal Syndrome• The development of acute renal failure in a patient who usually has advanced liver disease due to cirrhosis, severe alcoholic hepatitis, or (less often) metastatic tumor• The HepatoRenal syndrome usually represents the end-stage of a sequence of reductions in renal perfusion induced by increasingly severe hepatic injury.
Pathogenesis• Arterial vasodilatation in the splanchnic circulation, which is triggered by portal hypertension, appears to play a central role in the hemodynamic changes and the decline in renal function in cirrhosis• The presumed mechanism is increased production or activity of vasodilators, mainly in the splanchnic circulation, with nitric oxide thought to be most important• Splanchnic arterial vasodilatation triggers intense homeostatic neurohumoral response causing sodium retention and solute-free water retention and finally, severe renal vasoconstriction due to increase in plasma renin activity and norepinephrines.
• Most accepted theory considers that renal vasoconstriction is consequence of the extreme under filling of systemic arterial circulation, which activates homeostatic vasoconstrictive systems, whose effect on kidney cannot be counterbalanced by either renal or systemic vasodilators.
Pathophysiology• Incidence of HRS in patients with cirrhosis hospitalized for Ascites is approx 10%.• Probability of developing HRS in patients with cirrhosis and Ascites is 18% at 1 yr and increase to 39% at 5 yrs.• Renal failure is associated with oliguria, marked Na+ retention, and spontaneous dilutional hyponatremia.
Types Of HepatoRenal Syndromes Type 1• Rapid and progressive impairment of renal function as defined by doubling of initial S. Creatinine to level higher than 2.5 mg/dl or 50% reduction of initial 24-h creatinine clearance to a level lower than 20 ml/min < 2 wks.• Rapid and aggressive course ( very ill in days or weeks)• Develops spontaneously• large volume paracentesis (>5 L) without I.V. albumin may precipitate in 20% cases.
• Bacterial infection, particularly SBP recognized as precipitating cause( 1/3 rd cases with SBP)• Without treatment median survival rate is 1 month.• MELD score with type of HRS have an independent prognostic value in survival.• Most patients with Type 1 HRS have MELD score of >20.
Type 2• Impairment in renal function with serum creatinine >1.5 mg/dl that does not meet criteria for type 1.• Less severe and stable reduction in GFR• Serum creatinine levels are usually less than 2.0 mg/dl.• Main clinical consequence is diuretic-resistant ascites due to combination of intense sodium retention and reduced GFR.• Expected survival is longer• If MELD score >20 in type 2 HRS associtaed with worse prognosis.
Parameters associated with a higher risk for HRS development in non-azotemic patients with cirrhosis and Ascites.• Previous episodes of Ascites• Poor nutritional status• Moderately increased BUN( 30 mg/dl)• Moderately increased creatinine( 1.5 mg/dl)• Low serum Na+(<130 Meq/L)• Low urinary Na+ excretion(<10 Meq/l)• High plasma renin activity• Low MAP(<85mm Hg)• Reduced solute-free water excretion after water load(<3 ml/min)• Increased plasma norepinephrines
• Presence of esophageal varices.• MELD score.
Diagnostic CriteriaMajor:• Low GFR, as indicated by S. creat >1.5 Mg/Dl or 24-h Creatinine Clearance < 40 Ml/min• Absence of shock, on- going bacterial infection, fluid losses, and current treatment with neprotoxic drugs• No sustained improvement in renal function( decrease in S. creatinine to < 1.5 mg/dl or increase in Creatinine clearance to >40 ml/min) following diuretic withdrawal and expansion of plasma volume with 1.5 L of plasma expander.• Proteinuria <500 Mg/d and no USG evidence of obstructive uropathy or parenchymal renal
Prevention• HRS can be prevented in 2 clinical settings:• SBP- administration of albumin( 1.5 g/kg body weight at diagnosis of infection and 1 g/kg body weight 48 hrs later), prevents circulatory dysfunction.• Incidence of HRS in SBP patients receiving albumin together with antibiotics is 10% compared to 33% not receiving albumin.• Hospital mortality lower(10% in patients receiving albumin Vs not receiving same(29%)• Acute Alcoholic Hepatitis: administration of pantoxifylline, an inhibitor of TNF-Alpha( 400 mg TID orally for 28 d) reduces incidence of HRS from 35% to 8% and mortality from 46% to 24%.
Treatment• Diuretics should be held• Saline infusions should not be administered, as it leads to increase in edema and Ascites. because of dilutional hyponatremia in these patients, water restriction (1000 ml/d) should be instituted.• Early identification of bacterial infections and treatment with the broad spectrum antibiotics should be started.• Patient should be evaluated for liver transplant and if already in the list, the status should be updated. specific treatment with vasoconstrictors and albumin should be initiated as soon as the diagnosis is suspected.
Treatment• Pharmacologic therapy:• While considering pharmacologic therapy, patients should be evaluated for Liver transplant.• Renal vasodilators:• Dopamine: in suppressor doses, but studies shown no or minimal effect on the GFR, thus no data to support use in clinical practice.• Prostaglandins and PG analog: rationale in use is renal vasoconstriction in HRS is partially secondary to reduced intrarenal synthesis of PGs.• No consistent beneficial effect on renal function were observed after IV or intra-arterial administration of PGA1 or PGE2.
• Oral administration of misoprostol(PGE1 analog) was found to improve renal function in 1 study but was not confirmed in subsequent investigation.• Side effect of PGs- Diarrhea.• Other approaches such as endothelin blockers(BQ123) and N-acetyl cysteine are promising but larger trails needed for confirmation.
• Systemic vasoconstriction with plasma expansion seem to be best therapy, particularly in HRS type 1.• Vasoconstrictors- vassopressin analogs( terlipressin) vasoconstictor effect by action on V1 receptors with low V2 receptor agonist activity• Somatostatin analog( octreotide) acts as glucagon inhibitors and alpha adrenergic agonists( midodrine and noradrenaline), cause vasoconstriction by acting on alpha receptors.• Ischemic side effects of terlipressin is less as compared to vassopressin and ornipressin( only 5-10% compared to 30-40%)
• Administration of terlipressin and albumin is associated with significant improvement in GFR and reduction of S. creatinine <1.5 mg/dl in patients with Type 1 HRS.• Patient with child-pugh score >13 and those not receiving albumin do not respond well.• Chance of recurrence after stopping the treatment• Treatment with terlipressin can be stopped, if S. creatinine does not decrease by 50% after 7 days of maximum dose or if no reduction in S. creatinine after first 3 days.
• If early response present treatment, treatment should be extended until reversal of HRS or maximum of 14 days.• Administration of midodrine with octreotide and albumin improves renal function.• Treatment titrated based on MAP, optimum increase is by at least 15mm Hg.• Therapeutic approach limited to only 2 studies, with total of less than 20 patients.• In all cases there was marked improvement in the GFR and renal perfusion and suppression of renin, aldosterone, norepinephrine and AVP to normal or near normal levels.• Octreotide is ineffective when administered alone.
• Administration of noradrenaline ( 0.5-3 mg/h) with albumin for minimum of 5 days resulted in increase in MAP, improvement of renal function, marked reduction in renin and aldosterone.• Titration of Noradrenaline based on increase in MAP of atleast 10 mm Hg or increase in 4-h urine output to more than 200 ml.• Single episode of reversible myocardial hypokinesia., no ischemic events.• Limited validity secondary to lack of large randomized studies.
Recommendations• These drugs should be used for at least 7-10 days, as renal improvement occurs slowly.• Therapy should be aimed at reducing S. creatinine level below 1.5 mg/dl.• Concomitant administration of albumin(1g/Kg on first day, followed by 20-40 g/d) as plasma expander.• Because of limited information and possibility of side effects, treatment of vasoconstrictors should be restricted to patients with Type 1 HRS.
Recommended Dosages• Midodrine: 7.5 mg orally TID with an increase to 12.5 mg TID if needed and octreotide: 100 mcg Sc TID with increase to 200 Mcg TID, if needed.• Noradrenaline: Titration of 0.5 to 3 mg/hr continuous IV infusion.• Terlipressin: 0.5 mg IV every 4 hrs, can increase dose in stepwise manner (i.e. every 2 days) to 1 mg/4 hrs and than up to 2 g/4 hrs in cases where there is no reduction in S. creatinine.
Therapeutic Response to Vasoconstrictors in HepatorenalSyndrome Parallels Increase in Mean Arterial Pressure: A Pooled Analysis of Clinical Trials. Velez JC, Nietert PJ.• AIM: To explore across all tested vasoconstrictors whether achievement of a substantial increase in arterial blood pressure is associated with recovery of kidney function in HRS.• RESULT: An increase in MAP is associated strongly with a decrease in serum creatinine level, but is not associated with an increase in urinary output. Most studies tested terlipressin as vasoconstrictor, whereas fewer studies tested
ornipressin, midodrine, octreotide, or norepinephrine. Furthermore, a decrease in PRA correlated with improvement in kidney function.• CONCLUSIONS: An increase in MAP during vasoconstrictor therapy in patients with HRS is associated with improvement in kidney function across the spectrum of drugs tested to date. These results support consideration for a goal- directed approach to the treatment of HRS.
Hepatorenal syndrome: do the vasoconstrictors work? Leung W, Wong F. Gastroenterol Clin North Am. 2011 Sep;40(3):581-98.• Abstarct: The development of hepatorenal syndrome (HRS) is related to many changes associated with advanced cirrhosis. Because vasoconstrictors correct systemic and splanchnic hemodynamic abnormalities, they are effective treatments for HRS, although only in approximately 40% of HRS patients. Emerging data show that combination treatment with vasoconstrictors and TIPS may yield better outcomes than either alone. All HRS patients should be assessed for liver transplantation. Reversing HRS before transplantation is associated with better long-term survival.
Transjugular intrahepatic Portosystemic shunt (TIPS)• Rationale is by reducing the portal pressure may improve circulatory function and suppress RAAS and SNS activities.• TIPS may improve Renal function and GFR as well as reduce activities of RAAS and SNS in patients with Type 1 HRS.• Studies with assessing TIPS for type 1 HRS have included patients with relatively preserved liver function.• An approach combining TIPS with vasoconstrictive therapy had excellent outcomes with improvement in renal function.
• In Type 2 HRS, TIPS reduce ascites and improve renal function.• One report, however, suggested that the reduction in intrahepatic pressure induced by this modality may prevent the development of the hepatorenal syndrome. This retrospective study evaluated 204 patients with variceal bleeding who were treated with either a portasystemic shunt or sclerotherapy (or other nonshunt modality) . Shunting was associated with a lower incidence of ascites (15 versus 73 percent) and hepatorenal syndrome (4 versus 21 percent), a higher incidence of encephalopathy, and no difference in overall patient survival.
Dialysis• HD and PD- sporadic cases of improvement of renal function.• HD not routinely recommended for HRS but can be option for liver transplant candidates as bridge to transplantation• Especially inpatients who failed vasoconstrictive and TIPS therapy or develop severe volume overload, metabolic acidosis, or refractory hyperkalemia.• Data on extracorporeal albumin dialysis system, that is molecular adsorbent recirculating system (MARS) seems beneficial but only 1 study available.• Albumin dialysis is associated with increased BP secondary to ability of the albumin to bind vasodilators.
Liver Transplantation• Best treatment option• Long term outcomes are good, survival 85% at 1 yr and 73% at 3 yrs.• Presence of HRS before the transplantation increase the morbidity and mortality.• Patients with HRS type 1 have poor prognosis, thus should be given immediate priority for liver transplantation.• Patients with HRS type 2 but MELD score >20, should be given priority too.• If patients treated successfully with pharmacological therapy, outcomes after liver transplant are similar to those without HRS.
Combined liver– kidney transplantation isindicated for those with irreversible kidney injury.Otherwise, there is some merit in performing aliver transplant first and only considering akidney transplant later.
References• Schiff’s disease of the liver, tenth edition, Authers: Eugene R. Schiff et al• Text book of Gastroenterology, fifth edition, Authers: Tadataka Yamada et al• Hepatorenal Syndrome, Charles KF Ng, Michael HM Chan, Morris HL Tai, and Christopher WK Lam*• Levinsky NG: Nephrology Forum: Refractory ascites in cirrhosis. Kidney Int 14:93–102, 1978• DiBona GF: Nephrology Forum: Renal neural activity in hepatorenal syndrome. Kidney Int 25:841–853, 1984• Fullen WD: Hepatorenal syndrome: reversal by peritoneovenous shunt. Surgery 82:337–341, 1977• Pladson TR, Parrish RM: Hepatorenal syndrome: recovery after peritoneovenous shunt. Arch Intern Med 137:1248–1249, 1977• Levy M: Hepatorenal syndrome, in The Kidney: Physiology and Pathophysiology (2nd ed), edited by Seldin DW, Giebisch G, New York, Raven, 1992, pp 3305–3326• Epstein M: Hepatorenal syndrome, in The Kidney in Liver Disease (3rd ed) edited by Epstein M, Baltimore, Williams & Wilkins, 1988, pp 89–118