Hepatorenal Disorders
David J. Leehey, M.D.
Professor of Medicine
A patient
A 65‐year‐old male was admitted to LUMC in 2/06 with upper GI bleeding and ascites. He was found to have end‐stage alcoholic cirrhosis complicated by encephalopathy, ascites, and esophageal variceal bleeding. In addition, he had renal failure. Urinalysis showed 3+ protein and > 50 RBC/hpf as well as hyaline and granular casts. Urine sodium concentration was < 10 mmol/L. The urine protein‐
to‐creatinine ratio on a random urine specimen (urine Pr/Cr) was 667/144.8 (mg/mg). Hemodialysis was instituted.
What do you recommend next?
• Continue hemodialysis, list for liver transplant alone.
• Continue hemodialysis, list for combined liver‐
kidney transplant
• Renal biopsy to aid in management
• Palliative care
What is hepatorenal syndrome (HRS)?
• HRS in its pure form is functional renal failure due to reversible renal vasoconstriction. • The kidneys are structurally normal and at least in the early part of the syndrome, tubular function is intact, as reflected by avid sodium and water retention and oliguria. • Kidneys from patients with HRS transplanted into patients with end‐stage renal failure and a healthy liver resumed normal function (Koppel et al. NEJM 1969). What is the cause of renal vasoconstriction?
The cause of renal vasoconstriction is unknown but may involve both increased vasoconstrictor and decreased vasodilator factors acting on the renal circulation. There are three factors predominantly involved in its pathogenesis. These are: (1) Hemodynamic changes that decrease renal perfusion pressure. (2) Stimulated renal sympathetic nervous system. (3) Altered balance of renal vasoactive mediators.
Regulation of the renal circulation in cirrhosis is a balance
between vasoconstrictors and vasodilators
Administration of NSAID (indomethacin) to patients with cirrhosis causes
acute renal failure (“drug-induced HRS”)
(adapted from Boyer and colleagues 1979).
The spectrum of alterations in the renal circulation in cirrhosis
What is the cause of arterial vasodilation?
• Splanchnic vasodilatation
– Bacterial translocation across the intestinal wall increases circulating endotoxins.
– Endotoxins induce nitric oxide synthase (iNOS) which produces nitric oxide, a very potent vasodilator. – In experimental cirrhosis due to carbon tetrachloride, administration of L‐NAME, an inhibitor of nitric oxide synthesis, reverses the vasodilatory state. Pathophysiologic mechanisms of hepatorenal syndrome (HRS)
Wadei H M et al. CJASN 2006;1:1066-1079
Determining kidney function in patients with cirrhosis
• Creatinine assays are subject to interference by chromogens (e.g., bilirubin) • Decreased hepatic production of creatine • The edematous state that complicates end‐stage liver disease leads to larger volume of distribution of creatinine and lower serum creatinine concentration
Proulx et al. Nephrology Dialysis Transplantation 2005
Hepatorenal syndrome (HRS)
• HRS is a form of acute (type 1) or subacute (type 2) renal failure characterized by severe renal vasoconstriction, which develops in decompensated cirrhosis or fulminant liver failure. • In its severe form (type 1 HRS), nearly half of patients die within 2 weeks of diagnosis • The annual incidence of HRS ranges between 8% and 40% in cirrhosis depending on the MELD score
• The frequency of HRS in severe acute alcoholic hepatitis and in fulminant liver failure is about 30% and 55%, respectively Munoz S. Medical Clinics of North America July 2008
Munoz S. Medical Clinics of North America July 2008
Major diagnostic criteria for hepatorenal syndrome
• Cirrhosis or fulminant liver failure with ascites • Serum creatinine > 1.5 mg/dL • No improvement in serum creatinine (decrease to a level of <1.5 mg/dL) after at least 2 days of diuretic withdrawal and volume expansion with albumin (1 g/kg/day up to a maximum of 100 g/day for 2 days)
• Absence of shock • No current or recent treatment with nephrotoxic drugs • Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (<50 RBC/high power field) and/or abnormal renal ultrasonography
Angeli et al. Journal of Hepatology February 2008
Minor diagnostic criteria for hepatorenal syndrome
• Urine volume < 500 mL/24 h
• 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
(Ascites Club 1996)
Angeli et al. Journal of Hepatology February 2008
Classification of the hepatorenal syndrome
• Type 1: cirrhosis with rapidly progressive acute renal failure • Type 2: cirrhosis with subacute renal failure • Type 3: cirrhosis with types 1 or 2 HRS superimposed on chronic kidney disease or acute renal injury
• Type 4: fulminant liver failure with HRS Munoz S. Medical Clinics of North America July 2008
Type 1 hepatorenal syndrome
• The serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks • Median survival of only 1 to 2 weeks
• It can be precipitated by spontaneous bacterial peritonitis and variceal hemorrhage • In some cases acute hepatic injury, superimposed on cirrhosis, may lead to liver failure and HRS Munoz S. Medical Clinics of North America July 2008
Type 2 hepatorenal syndrome
• Serum creatinine increases slowly and gradually during several weeks or months
• Many patients with type 2 HRS eventually progress to type 1 HRS because of a precipitating factor • The median survival of type 2 HRS is about 6 months Munoz S. Medical Clinics of North America July 2008
Type 3 hepatorenal syndrome
• 85% of end‐stage cirrhotics have intrinsic renal disease on renal biopsy
• Patients with long‐standing diabetic nephropathy, obstructive renal disease, or chronic glomerulonephritis can develop HRS from a precipitating event or worsening liver failure Munoz S. Medical Clinics of North America July 2008
Type 4 hepatorenal syndrome
• More than half of patients with fulminant hepatis develop HRS, although the frequency varies depending on the etiology
Munoz S. Medical Clinics of North America July 2008
Causes of acute renal failure in patients with cirrhosis
• Acute tubular necrosis (ATN)/acute kidney injury (AKI) (41.7%)
• Pre‐renal failure (38%)
• Hepatorenal syndrome (20%)
• Post‐renal failure (0.3%)
Moreau et al. Hepatology 2003
What are the other hepatorenal disorders?
Indications for combined liver‐kidney transplantation (CLKT)
• Combined end‐stage liver disease (ESLD) and end‐
stage kidney disease (ESKD).
• Hereditary diseases such as oxalosis, amyloidosis, severe polycystic liver disease, and complement H deficiency in the setting of ESKD. • Controversy exists as to allocation of donor kidneys to patients with ESLD with hepatorenal syndrome (HRS), because most of these patients will recover renal function after liver alone transplantation (LAT).
Disparity in CLKT utilization among US centers
Mehta SA, Leehey DJ. Disparity in utilization of combined kidney-liver
transplantation in the U.S. Clin Transplant 23(6):938-42, 2009.
Recovery of HRS after LAT
• In a seminal report published in 1973, 3 patients with progressive renal failure and advanced cirrhosis underwent LAT, after which they regained nearly normal kidney function. Iwatsuki S et al. Recovery from "hepatorenal syndrome" after orthotopic liver transplantation. N Engl J Med 1973;289:1155‐9.
Recovery of renal function after prolonged HRS
• In a more recent report, a 37‐year‐old patient with alcoholic cirrhosis and HRS requiring HD for more than 8 months underwent LAT, after which renal function recovered.
Storm C, et al. Immediate recovery of renal function after orthotopic liver transplantation in a patient with hepatorenal syndrome requiring
hemodialysis for more than 8 months. Transplant Proc 2007; 39: 544‐6.
Analysis of UNOS Database
• UNOS data during the period 1/1/2000 through 9/3/2010 were analyzed to determine kidney allograft survival (defined as allograft failure or patient death) and patient survival in patients with kidney disease undergoing CLKT, liver alone transplantation (LAT), and kidney alone transplantation (KAT).
Leehey DJ, Hou SH, Kramer HJ. ASN 2011
• Etiology of kidney disease was available for liver transplant recipients who also received a kidney transplant
• A recipient was considered to have HRS if etiology of kidney disease was described as “hepatorenal syndrome” or “kidney disease due to liver failure”
• Etiology of kidney disease among liver transplant recipients who did not receive a kidney was not available
Results
• Among 54,676 liver transplants performed, 8978 (16.4%) recipients had kidney disease, defined as receiving dialysis (3411 patients) or serum creatinine > 2.5 mg/dl at wait‐listing (5567 patients). • 3893 (43.4%) recipients with kidney disease underwent CLKT, of whom 498 (12.8%) had a reported diagnosis of HRS; mean age was 52.4 + 10.3 (range 20‐75) years, 34% were female, and 22% had diabetes. • During the same time period, 92,771 dialysis‐dependent and 7,701 non‐dialysis‐dependent patients without liver disease received deceased donor KAT.
One‐year allograft failure* (%)
*Allograft failure or patient death
Five‐year allograft failure* (%)
*Allograft failure or patient death
One‐year patient mortality (%)
Five‐year patient mortality (%)
30
25
20
Dialysis
No dialysis
15
10
5
0
CLKT
LAT
KAT
What is this animal?
“A camel is a horse designed by committee”
– Sir Alec Issigonis
Hepatorenal syndrome: the 8th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group
Mitra K Nadim, John A Kellum, Andrew Davenport, Florence Wong, Connie Davis, Neesh Pannu, Ashita Tolwani, Rinaldo Bellomo, Yuri S Genyk and The ADQI Workgroup. Critical Care 16:R23, 2012.
“Of the 30 questions considered, we found inadequate evidence for the majority of questions and our recommendations were mainly based on expert opinion”
Grading evidence and recommendations (adapted from the GRADE system)
Quality of Evidence
• High (A): large, high quality randomized control trials. We are confident that the true effect lies close to that of the estimate of the effect. • Moderate (B): Limited or conflicting data from randomized control trials. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • Low (C): Observational studies or very small randomized control trials. The true effect may be substantially different from the estimate of the effect. • Very low (D): Expert opinion. The estimate of effect is very uncertain, and often will be far from the truth. Grading Recommendation
• Strong (1) 'We recommend'
Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful and effective • Weak (2) 'We suggest'
Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment Some of the evidence
•
•
•
•
We recommend that patients with type‐1 HRS be optimally resuscitated with albumin (initially 1 g of albumin/kg for two days, up to a maximum of 100 g/day, followed by 20 to 40 g/day) in combination with a vasoconstrictor (1A), preferentially terlipressin (2C)
We recommend use of a transjugular intrahepatic portosystemic shunt (TIPS) as a treatment option for patients with type‐2 HRS with refractory ascites who require large‐volume paracentesis (1C) We suggest liver transplantation alone for candidates with type‐1 HRS for less than four weeks and simultaneous liver‐kidney (SLK) for those at risk for non‐recovery of renal function (2D) We recommend withholding renal replacement therapy (RRT) in patients with decompensation of cirrhosis who are not candidates for liver transplantation (1D) Prevention of HRS
•
Prophylaxis against bacterial infections, especially spontaneous bacterial peritonitis (SBP)
– Variceal bleeding
– History of previous SBP. •
Volume expansion
– Patients with SBP should be volume expanded with albumin (1–1.5 g/kg over 1–3 days) at diagnosis to prevent circulatory dysfunction, renal impairment, and mortality.
– Use of albumin as fluid replacement in patients undergoing large volume paracentesis (8 g/L of ascitic fluid removed) prevents paracentesis ‐induced circulatory dysfunction. •
Judicious use of diuretics
– Renal impairment occurs in ∼20% of patients with ascites. – It develops when the rate of diuresis exceeds the rate of ascites reabsorption, leading to intravascular volume depletion. – Diuretic resistance = failure to respond to furosemide 160 mg/daily plus spironolactone 400 mg/daily. However, beware if no or minimal edema!
•
Avoid use of nephrotoxic drugs
– Aminoglycosides, colistimethate (renal toxins)
– NSAIDs (inhibit intrarenal prostaglandins) Medical treatment of HRS
•
•
•
•
•
•
Treat underlying cause of liver disease (abstinence from alcohol, steroids or other immunosuppressives if indicated)
Treat hypovolemia (diuretics or gastrointestinal bleeding). Unless clearly contraindicated (pulmonary edema), volume challenge with up to 1.5 L of isooncotic albumin. Treat hypotension. Increase mean arterial pressure at least 10 mm Hg by vasopressors (e.g., norepinephrine) Avoid nephrotoxins, treat infection with non‐nephrotoxic antibiotics
Consider paracentesis. A decrease in abdominal pressure can decrease renal venous pressure and improve renal blood flow and GFR. A fall in systemic BP must be prevented by albumin replacement and/or pressors.
Pharmacological treatment to increase renal blood flow
– Indirectly by splanchnic vasoconstriction (vasopressin analogues, octreotide)
– Directly by systemic vasoconstrictors (midodrine, norepinephrine)
Midodrine/octreotide
• In three pilot studies with a total of 79 patients, a complete recovery of renal failure was observed in 49% of patients.
• In most patients midodrine administration started at 5‐10 mg t.i.d. orally, with the goal of increasing the dose to 12.5 or 15 mg t.i.d. if a reduction of serum creatinine was not observed • Octreotide administration started at 100 μg subcutaneously t.i.d. with the goal of increasing the dose to 200 μg subcutaneously t.i.d. if a reduction of serum creatinine was not observed
Angeli et al. Journal of Hepatology February 2008
Midodrine, octreotide, and albumin cocktail
Skagen et al. J Clin Gastroenterol 2009
A patient
A 65‐year‐old male was admitted to LUMC in 2/06 with upper GI bleeding and ascites. He was found to have alcoholic cirrhosis complicated by encephalopathy, ascites, and esophageal variceal bleeding. In addition, he had renal failure. Urinalysis showed 3+ protein and > 50 RBC/hpf as well as hyaline and granular casts. Urine sodium concentration was < 10 mmol/L. The urine protein‐
to‐creatinine ratio on a random urine specimen (urine Pr/Cr) was 667/144.8 (mg/mg). Hemodialysis was instituted.
What do you recommend next?
• Continue hemodialysis, list for liver transplant alone.
• Continue hemodialysis, list for combined liver‐
kidney transplant
• Renal biopsy to aid in management
• Palliative care
A renal biopsy was performed
LIGHT MICROSCOPY:
‐ 10 glomeruli per level, of which 4 (40%) showed global sclerosis. ‐ 4 other glomeruli showed segmental early tuft necrosis (concentration of polymorphonuclear leukocytes with nuclear dust and fibrin)
‐ Mesangial and a capillary proliferation. One small cellular crescent involving 20% of the Bowman's capsule. No evidence for vasculitis or amyloid.
ELECTRON MICROSCOPY:
‐ 2 glomeruli were examined and revealed abundant mesangial
immune‐complex deposits; no deposits seen in the glomerular basement
membrane. There was a partial effacement of the epithelial cell foot processes.
IMMUNOFLUORESCENCE STUDIES:
‐ 6 glomeruli per level, of which 2 show global sclerosis. ‐ Diffuse and granular stain for IgA (3+), IgM (trace), both light chains (3+), C3 (3+), C1q (trace) and fibrinogen predominantly in the mesangial matrix. IgG negative.
What do you recommend next?
• Continue hemodialysis, list for liver transplant alone.
• Continue hemodialysis, list for combined liver‐
kidney transplant
• Renal biopsy to aid in management
• Palliative care
Clinical course
Subsequently, he was treated with corticosteroids and also received one dose of intravenous cyclophosphamide. He did not improve and required hemodialysis for 2.5 months. He was diagnosed with end‐stage cirrhosis and end‐stage renal disease and was considered for combined liver‐kidney transplant. On 4/27/06 he underwent liver transplant alone. He remained on dialysis until 5/9/06, at which time dialysis was no longer required. He is being maintained on immunosuppression with mycophenolate and tacrolimus. His serum creatinine decreased to 1.2 mg/dL and has been stable at this level over the following 6 years.
What did he have?
IgA nephropathy complicating alcoholic liver cirrhosis plus hepatorenal syndrome, which both improved after liver alone transplantation
Another patient
•
A 57‐year‐old man with a history renal cell Ca and horseshoe kidney, s/p partial nephrectomy (3/2008), alcoholic cirrhosis, admitted from GI clinic on 8/18/11 for jaundice, fever, and worsening liver function. He was treated for cholangitis with improvement. Transjugular liver biopsy was performed on 8/22/11 which revealed acute alcoholic and cholestatic hepatitis superimposed on cirrhosis. He was started on a prednisolone taper and diuretics (Lasix and spironolactone). He was readmitted 9/3/11 for SBP and worsening liver failure. The serum creatinine on admission was 2 mg/dL which improved to 1 mg/dL, but then increased again to 4 mg/dL. He was non‐oliguric. Urinalysis showed 1+ protein and 24h urine protein was 442 mg. He had prerenal urinary indices. On exam he was markedly jaundiced with 2+ ascites and minimal edema. He was diagnosed with HRS type 1, with evidence of additional acute kidney injury (AKI). He did not respond to octreotide/midodrine/albumin, developed oliguria, and was begun on hemodialysis on 9/15/11. Due to likelihood of renal functional recovery with liver transplantation, renal service recommend liver transplant alone. However he underwent combined liver and kidney transplant on 9/27/11. He continued to require dialysis for several weeks post‐operatively but was able to discontinued dialysis on 11/3/11 . His serum creatinine is currently in the 2.5 mg/dL range.
CLKT in HRS
Courtesy of S. Hou