RAI & HRS: Relationship Between Relative Adrenal Insufficiency and Failure of Treatment in Hepatorenal Syndrome
Condition: Liver Cirrhosis; Acute Kidney Injury; Hepato-Renal Syndrome
MeSH terms: Liver Cirrhosis; Hepatorenal Syndrome; Acute Kidney Injury; Adrenal Insufficiency; Syndrome
Study type: Observational

Summary: 
      Hepatorenal syndrome is a life-threatening medical condition and a serious complication of
      advanced liver scarring (cirrhosis). It consists of a deterioration of the function of the
      kidneys caused by a severe alteration in the circulation (blood flow to the kidneys) due to
      liver cirrhosis. Only around half of the patients respond to treatment which consists of
      intravenous medication. Moreover, the adrenal glands, which are located on the kidneys, also
      suffer an alteration in the blood flow leading to deterioration in their function as well.
      Thus, these patients produced less cortisol than needed; this situation is called "relative
      adrenal insufficiency". Cortisol is an important hormone necessary in extreme situations such
      as severe diseases. This is a study which will assess the relationship between the presence
      of adrenal dysfunction and failure to treatment in patients with hepatorenal syndrome.
    

Detailed description: 
      This is a prospective, observational, descriptive, clinical study.

      This is a single centre study. All patients admitted to the South West Liver Unit with
      decompensated cirrhosis will be screened according to their serum creatinine (sCr) level
      taken as part of standard of care at admission or during their hospitalization.

      All patients with AKI stage 2-3 or with stage 1 and serum Creatinine >133 µmol/L who give
      consent to participate or consent is given by legal representative. Patients should meet all
      the inclusion criteria and none exclusion criteria.

      The consent can be received by a medical doctor or by a research nurse involved in the study.
      The details will be recorded on the study delegation log.

      Patients will be followed up during admission. Decompensation episodes including development
      of hepatic encephalopathy, worsening ascites, jaundice, GI bleeding related to portal
      hypertension, and infections will be recorded during follow up. Follow up finishes when the
      patient is discharged.

      AKI is defined as an increase of at least 26 µmol/L or a percentage increase of at least 50%
      from baseline sCr value, within 48 hours. Baseline value should have occurred within the
      previous 7 days. When baseline sCr is not known investigators diagnose AKI when sCr is higher
      than 106 µmol/L.

      All patients with AKI will have the following tests taken at admission or when they develop
      AKI, as per standard of care: Full blood count; electrolytes; liver profile including
      bilirubin, GGT, ALP, AST, and ALT; coagulation screen including PT, INR and APTT; C-reactive
      protein; blood cultures; glucose; bone profile, including phosphate and calcium.

      Stages of AKI are defined as:

        -  Stage 1: increase of sCr ≥26 μmol/L or an increase in sCr ≥1.5-fold to 2-fold from
           baseline. When baseline value is not known, sCr>106 μmol/L.

        -  Stage 2: increase of sCr >2-fold to 3-fold from baseline. When baseline value is not
           known, sCr>176 μmol/L.

        -  Stage 3: increase of sCr >3-fold from baseline or sCr ≥353 μmol/L or initiation of renal
           replacement therapy. When baseline value is not known, sCr>353 μmol/L.

      Investigators will include a participant when they are diagnosed with AKI stage 2 or 3 or
      with AKI stage 1 with persistent sCr >133 µmol/despite initial measures, then baseline blood
      samples and urine sample will be taken and short synacthen test (SST) will be performed as
      per standard of care. SST consists of taking a sample for baseline total cortisol followed by
      intravenous administration of 250 µg of corticotropin followed by a new sample taken 60
      minutes later to test peak total cortisol.

      Extra blood samples will be taken when the patient is included and they include: plasma renin
      activity, aldosterone, vasopressin, norepinephrine, tumour necrosis factor-alpha,
      Interleukin-6, Interleukin-12, Interleukin-10, blood sample for detection of bacterial DNA,
      urinary sample to detect neutrophil gelatinase-associated lipocalin (NGAL).

      Samples should be taken within 48 hours of diagnosis of AKI and always before treatment with
      terlipressin is started.

      Patients will be managed according to our local guidelines and national and international
      standards. Human albumin (HAS) will be administered at 1 gram per Kilogram of weight in those
      participants with AKI stage 2-3 or those with AKI stage 1 who do not improve or progress. If
      there is no response after 48 hours of administration of HAS and HRS criteria are met, then
      vasoconstrictor treatment with terlipressin will be started.

      Response to treatment is defined as a reduction of at least 25% from pre-treatment value.
      Full response is met when sCr returns to a value lower than 26 μmol/L above the baseline
      value. Partial response is met when final sCr returns to a value higher than 26 μmol/L above
      the baseline value.

      During hospitalization vital signs and standard liver and renal tests will be recorded.

      All interventions and follow-up will be carried out during the hospitalization.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Hepatorenal syndrome is a life-threatening medical condition and a serious complication of
        advanced liver scarring (cirrhosis). It consists of a deterioration in the function of the
        kidneys caused by a severe alteration in the blood flow to the kidneys due to liver
        cirrhosis. Around half of patients respond to treatment. The adrenal glands (located on the
        kidneys), suffer a variation in blood flow leading to deterioration in their function. Thus
        these patients produce less cortisol than needed; this situation is called "relative
        adrenal insufficiency". Cortisol is an important hormone necessary in extreme situations
        such as severe diseases. This study is to assess the relationship between the presence of
        adrenal dysfunction and failure to treatment in patients with hepatorenal syndrome.
      
Biospecimen description: 
      -  Plasma renin activity: 0,5 mL of plasma EDTA

        -  Plasma norepinephrine: 1,3 mL of plasma EDTA

        -  Aldosterone: 0,5 mL of serum

        -  TNF-alpha: 0,5 mL of serum

        -  Interleukin-6: 0,3 mL of serum

        -  Interleukin-10: 0,3 mL of serum

        -  Interleukin-12: 0,5 mL of serum

        -  10 ml of urine will be centrifuged at 3000 rpm for 10 minutes at 4°C and storage
           specimens at - 80°C.