Jagmeet S Dhingra 1/2/2013

 45 yo hispanic male with long standing cirrhosis due to HepC and Alcohol  Multiple admissions for hepatic encephalopathy  Diuretic resistant ascites with therapeutic paracentesis every 2 months  Physical examination suggestive of volume overload with peripheral edema and ascites  Acute rise in Cr to 2.9 in 5 days from a baseline of found on outpatient labs  Baseline BP ’s  On lactulose at home.  Last LVP 1 week ago with 10 liter removal

 What to do and Whats going on. Options 1. I cant believe I am having another crappy night. 2. Do a detailed history and exam 3. Start normal saline at 150cc/hour-he is likely intravascularly depleted 4. Do a diagnostic paracentesis 5. Send of UA, urine lytes along with chemistries 6. Call the renal fellow

 AKI is a relatively frequent problem, occurring in approximately 20% of hospitalized patients with cirrhosis  Renal dysfunction (creatinine and blood urea nitrogen/azotemia) both powerful predictors of death in decompensated cirrhosis.  Higher serum creatinine consistently portends worse survival

 Hospitalized cirrhotic patients 20% present with AKI at admission  70 % develop with AKI during Admission  Patients admitted with SBP 41-56% have AKI  5-6% develop AKI after TIPS  Annals of Hepatology (3)

 During the history you obtain while trying to stay awake, he mentions he has been taking Ibuprofen for knee pain and has also been having some abdominal discomfort. Hasn’t noticed increased stool output on lactulose but they were black yesterday. Abdomen on exam is not tense but does have some generalized tenderness  What next

 Why couldn’t he come to hospital earlier in the day and why do I get all the train wrecks  Start normal saline at 150/hour. He is likely GI bleeding  Do a diagnostic paracentesis. This is likely peritonitis.  Its probably the ibuprofen.  Send of labs and urine studies and start albumin  Call the renal fellow

 Nonsteroidal antiinflammatory drugs may also cause renal failure in patients with cirrhosis, since their kidney function is extremely dependent on renal prostaglandin synthesis.  Patients who have ascites, particularly those with hyponatremia, bacterial infections, gastrointestinal bleeding, or severe sodium retention, are at high risk for renal failure, as are all patients hospitalized for acute decompensation of cirrhosis

 Creatinine is derived from creatine, mostly synthesized by the liver.  Patients with liver disease tend to have lower creatine synthesis and consequently, lower serum creatinine values for any given level of GFR.  These lower values are compounded by the loss of muscle mass that is common in patients with progressive chronic liver disease.  Also have a degree of creatinine dilution caused by the accumulation of peripheral edema and ascites.

 Clinical chemistry laboratories typically measure serum creatinine by a modified Jaffe colorimetric assay, which depends on a color change that can be influenced by noncreatinine chromogens such as bilirubin, particularly with serum bilirubin concentrations >10 mg/dl. This effect of bilirubin reduces the measured creatinine value. Alternative is to measure it enzymatically  Serum creatinine and estimated GFR calculated using serum creatinine overestimate actual kidney function.

 Likewise, an increase in serum creatinine concentration of 0.3 mg/dl (i.e., corresponding to Acute Kidney Injury Network stage 1 AKI) represents a much greater decrease in kidney function in cirrhotic patients compared with others who develop AKI

 Electrolytes and protein should be measured (preferably in 24-hr urine samples) in all patients with renal failure;  Significant proteinuria (>500 mg of protein/day) and urine-sediment abnormalities usually indicate parenchymal renal disease.  A renal biopsy is helpful when parenchymal renal disease is suspected because of proteinuria, hematuria, or both and  is also helpful in deciding on simultaneous kidney transplantation in candidates for liver transplantation;

 Intra-abdominal pressure may be increased in patients with cirrhosis because of the presence of tense ascites.  Although a typical compartment syndrome causing AKI may be associated with intra- abdominal pressures of 18 mmHg or greater, lower pressures can cause renal dysfunction, especially in the setting of systemic hypoperfusion or sepsis. Renal perfusion has been reported to improve after drainage of ascites.  Overzealous removal of ascites, even with colloid replacement, can lead to intravascular hypovolemia and ischemic AKI; Be careful with LVP

 His stool hemoccult turns out to be negative. He forgot to tell you he had also just started iron pills  His paracentesis suggests markedly elevated white count with high amount of polys  His urine sodium is less than 10 with a bland UA and no proteinuria

 It cant be 7 A.M soon enough  Start antibiotics and Albumin infusions  This is HRS due to the low urine sodium. Start midodrine and octreotide right away  He is septic. Given him 2 liter saline bolus and hold his diuretics  Transfer him to ICU for norepinephrine infusion for HRS  Call the renal fellow.

 HRS is a specific form of volume-unresponsive kidney injury in patients with progressive cirrhosis and ascites  Only around 50% of patients treated for HRS with vasoconstrictive agents respond to treatment with a reduction in serum creatinine

 1-year and 5-year probabilities of developing HRS in patients with ascites are approximately 20% and 40%,  Highest in patients with more marked sodium and water retention and marked activation of vasoconstrictive systems.  HRS is divided into two types (1 and 2) based on prognosis and clinical characteristics.  Survival of patients with HRS-1 is shorter than that of patients with HRS-2 (median survival 1.0 versus 6.7 months)

 Bacterial infection  SIRS/Sepsis  GI losses  Diuretics  GI bleeding  LVP  NSAIDs including COX-2  ACE inhibitors

 Presence of ascites is a prerequisite for the diagnosis of HRS because the same mechanisms that lead to ascites formation lead to HRS  HRS have advanced liver disease, as evidenced by the median Child-Pugh score in these patients being 11.2, and their low MAP (median, 74 mmHg), and low serum sodium (median, 127 mEq/L), findings that are consistent with the presence of vasodilatation (low MAP), sodium retention (ascites), water retention (dilutional hyponatremia), and renal vasoconstriction (HRS)

 Baseline SCr is a predictor of HRS reversal  The probability of HRS reversal decreases by 39% for each 1-mg/dL increase in baseline creatinine.  OLT is the only definitive therapy for HRS, only therapy associated with improvement in survival.  Important to try reverse HRS because improving renal function pretransplantation is associated with improved posttransplantation outcomes

 Vasoconstrictors used in the treatment of HRS for periods greater than 3 days are associated with increases in MAP, GFR, and serum sodium and decreases in SCr and plasma renin activity  Noradrenaline, in continuous infusion, has also been shown to ameliorate the hemodynamic /renal abnormalities in HRS as has the combination of midodrine.  They almost always require co administration of albumin

 Method to adjust the dose of vasoconstrictors is by monitoring MAP (an indirect indicator of vasodilatation), a method that has been used for adjusting the dose of midodrine plus octreotide, an alternative to terlipressin (not available in the US)

 The doses of octreotide and midodrine were titrated to obtain an increase in mean arterial pressure of at least 15 mm Hg.  Octreotide was administered subcutaneously at an initial dose of 100 μ g three times daily and then, if necessary,increased to 200 μ g three times daily.  Midodrine was administered orally at an initial dose of 7.5 mg three times daily and then, if need be, increased to 12.5 mg three times daily. In addition, an amount of 20 to 40 g/d of albumin was infused.

 Albumin is administered together with the vasoconstrictor.  The maintenance dose, once the diagnosis of HRS is established and vasoconstrictors are initiated, is 25 to 50 g/day.  Albumin may be discontinued if serum albumin concentration is greater than 4.5 mg/dL and should be withdrawn in case of pulmonary edema.

 In addition to serving as an intravascular volume expander, albumin also has binding sites for free radicals and toxins, and hence, in patients with liver failure, albumin infusions may help by increasing the capacity to bind such toxins

 Although intravenous infusion of crystalloid solutions can usually be safely given to patients with cirrhosis because of their systemic vasodilatation, any fluid bolus that initially expands the intravascular space will subsequently distribute to expand the entire extracellular space, worsening peripheral edema and ascites.  Overzealous fluid administration can also precipitate cirrhotic cardiomyopathy with heart failure and hypoxia because of hepatopulmonary syndrome.

 Treatment can be stopped if SCr does not decrease by at least 50% after 7 days at the highest dose, or if there is no reduction in creatinine after the first 3 days.  In patients with early response, treatment should be extended until reversal of HRS (decrease in creatinine below 1.5 mg/dL) or for a maximum of 14 days.  Vasoconstrictor therapy should be restarted if HRS recurs after discontinuation of therapy.  Once creatinine normalizes, TIPS should be considered, particularly if transplantation is not foreseeable in the near future and the patient has refractory ascites

 Patient is started on albumin infusions and antibiotics. He does not respond to albumin and renal consult is called for worsening creatinine.  A smart renal fellow ( now attending) starts the patient on midodrine octreotide with gradual uptitration of dose without much improvement  Transplant surgery and hepatology say patient not a transplant candidate due to active alcohol abuse

 When do I get off service. This guy is a rock. He will be here forever  Discuss with nephrology about initiating dialysis with worsening volume status  Family meeting and palliative care consult  Discuss with hepatology about TIPS

 In a large study involving 129 cirrhotic patients with varying degrees of baseline renal function, TIPS has been shown to improve renal function.  Patients with pre-treatment serum creatinine levels between 1.2 and 1.9 mg/dL had reduced mean levels of creatinine, from 1.5 to 1.1 mg/dL, and those with pre-TIPS creatinine levels > 2.0 mg/dL showed a reduction from 2.8 to 1.5 mg/dL.

 The prognosis for patients with cirrhosis and renal failure is poor.  The overall survival rate is approximately 50% at 1 month and 20% at 6 months.  Survival rates can differ according to the type of renal failure.  HRS is associated with the worst prognosis.  Type 1 HRS mortality 80% at 2 weeks with 10% 3 month survival  MELD score median survival 1 month if Meld 20 or more and 8 month if Meld less than 20

 The risk of the hepatorenal syndrome is substantial in patients with cirrhosis and spontaneous bacterial peritonitis but may be markedly reduced with the intravenous administration of albumin (1.5 g per kilogram of body weight at diagnosis and 1.0 g per kilogram 48 hours later).  The mechanism by which albumin prevents the hepatorenal syndrome is incompletely understood but may be related to albumin’s positive effects on circulatory function and other effects, such as its antioxidant properties

 Patients with ascitic fluid that contains less than 15 g of protein per liter and who have associated impairment of liver function, renal function, or both (a bilirubin level above 3 mg per deciliter, a Child–Pugh score greater than 10, a serum sodium level below 130 mmol per liter, or a serum creatinine concentration above 1.2 mg per deciliter, the long-term administrationof oral norfloxacin (400 mg per day) reducesthe risk of the hepatorenal syndrome and improves survival

 After informing the patient about his prognosis and outcome and that dialysis will not change his outcome due to his severe liver disease, patient and family decide to go with hospice care. Patient expired 1 week after discharge

 All AKI in Cirrhosis is not HRS  Look for a precipitating cause  Use volume judiciously  Avoid nephrotoxic agents  If starting vasoconstrictors, adjust doses based on repsonse. Do not leave patient on single fixed dose