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Ascites and Renal Failure unresponsive to standard treatment in patients with cirrhosis

Ascites and Renal Failure unresponsive to standard treatment in patients with cirrhosis. Journal Club 23/09/2019. Ilaria Giovo. Refractory ascites. Prognosis. 1). 3). 4). 2). Treatment strategies. Definition. Diagnostic criteria. Diagnostic Criteria. Prognosis. Definition.

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Ascites and Renal Failure unresponsive to standard treatment in patients with cirrhosis

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  1. Ascites and Renal Failure unresponsive to standard treatment in patients with cirrhosis Journal Club 23/09/2019 IlariaGiovo

  2. Refractory ascites Prognosis 1) 3) 4) 2) Treatment strategies Definition Diagnostic criteria

  3. Diagnostic Criteria Prognosis Definition Treatment strategies Refractory ascites (5-10% of cirrhotic patients with ascites) Ascites that cannot be mobilized or the early recurrence after paracentesis. - Diuretic-resistant ascites: lack of response to sodium restriction and diuretic treatment - Diuretic-intractable ascites: development of diuretic-induced complications that preclude the use of an effective diuretic dosage Portfolio Presentation You can simply impress your audience and add a unique zing and appeal to your Presentations. I hope and I believe that this Template will your Time, Money and Reputation. The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  4. Diagnostic Criteria Prognosis Treatment strategies Definition • Intensive diuretic therapy for at least one week and salt restriction (< 80 mEq/die) • Mean weight loss of <0.8 kg over four days and urinary sodium output less than the sodium intake • Reappearance of grade 2 or 3 ascites within four weeks of initial mobilization • Diuretic-induced complications: hepatic encephalopathy, renal impairment (creatinine > 2 mg/dL), hyponatremia (< 125 mEq/L), hypo- or hyperkalemia (< 3 or > 6 mEq/L) • Invalidating muscle cramps Portfolio Presentation You can simply impress your audience and add a unique zing and appeal to your Presentations. I hope and I believe that this Template will your Time, Money and Reputation. The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  5. Diagnostic Criteria Prognosis Definition Treatment strategies 1 0,8 0,6 0,4 0,2 0,1 0,0 You can simply impress your audience and add a unique zing and appeal to your Presentations. I hope and I believe that this Template will your Time, Money and Reputation. Survival of cirrhotic patients with and without refractory ascites ----- Non refractory ascites Refractory ascites p < 0.001 Probability 0 12 24 36 48 60 72 84 Months Salerno F et al. Am J Gastroenterol 1992

  6. Diagnostic Criteria Treatmentstrategies Definition • “False” refractory ascites: • Iatrogenic factors (NSAIDs, ACE-I, aminoglycosides) • Bacterial infections (SBP) • Compliance to low-sodium diet: evaluation of NaU/24 h • Refractory ascites confirmed • Diuretic discontinuation recommended(unless NaU > 30 mmol/day) The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  7. Diagnostic Criteria Treatment strategies Definition • Large volume paracentesis (LVP) + Albumin • More effective and safer than diuretic treatment (Ginés P et al. Gastroenterology 1987) • Recommended administration of human albumin* (8 g/L of ascites removed) to prevent post-paracentesis-induced circulatory disfunction (Bernardi M et al. Hepatology 2012) • Possible in outpatient setting • Ascites recurrence • No differences concerning hospital readmission rates and survival compared to diuretics (Ginés P et al. N Engl J Med. 2004) You can simply impress your audience and add a unique zing and appeal to your Presentations. I hope and I believe that this Template will your Time, Money and Reputation.

  8. 45 patients treated with SOC + long term albumin (20 g of human albumin twice a week) • 25 patients treated with SOC (Na restriction + diuretics) • Mean follow-up: 408 ± 394 days • Significant reduction of 24-month mortality in patients with cirrhosis and refractory ascites. • Reduced probability of hospitalization due to overt hepatic encephalopathy, ascites, SBP and other infections.

  9. Caraceni P, Riggio O, Angeli P, Alessandria C et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018 213 patients treated with SMT vs 218 with SMT + HA for 18 months • - Overall 18-month survival: 38% mortality reduction • - Rate of paracentesis: 54% reduction • - Incidence of refractory ascites: 57% reduction • - Reduction of: SBP, infections, AKI, HE (30-68%) • - Increase of QoL • Cost-effective: reduction in hospital admissions, days • In hospital, fewer paracentesis, fewer complications • (SBP, renal impairment, HE…)

  10. Diagnostic Criteria Treatment strategies Definition • TIPS • Better control of ascites than LVP • Lower rate of portal hypertension-related bleeding • Higher incidence of hepatic encephalopathy (HE) • Contraindications to TIPS placement • Impaired liver function (bilirubin > 3 mg/dL, C-P > 12, MELD > 15-18) • Age > 70 y • Recurrent encephalopathy • Concomitant cardiopulmonary disease You can simply impress your audience and add a unique zing and appeal to your Presentations. I hope and I believe that this Template will your Time, Money and Reputation. The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  11. Diagnostic Criteria Treatment strategies Definition • Peritoneovenous shunt • Fast ascites control • Renal function improvement • Shunt infection/thrombosis • Peritonitis • Unsatisfactory long-term results • Close patient monitoring/experienced centers • Currently not recommended by EASL guidelines. • Garbuzenko DV, Arefyev NO. Current approaches to the management of patients with cirrhotic ascites. World J Gastroenterol. 2019

  12. Diagnostic Criteria Treatment strategies Definition • - Alfapump • Significant reduction of number and volume of paracentesis • Improved QoL • Improved nutrition status • (Stirnimann G et al. Therap Adv Gastroenterol. 2017) • Technical difficulties • Renal impairment • (Solà E et al. Liver Transpl. 2017) • Unclear survival benefit INDICATION: patients with refractory ascites not amenable to TIPS, preferably in experienced centers • The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  13. Safe procedure • Reduction of albumin infusions • Improved QoL • Endotoxin infusion • Fever • Low BP • Currently not recommended by EASL guidelines.

  14. Diagnostic Criteria Treatment strategies Definition LIVER TRANSPLANTATION

  15. Diagnostic Criteria Treatment strategies Definition LIVER TRANSPLANTATION • 6-12 month survival in refractory ascites: 25-50% • 3-year survival after LT: 80% • Poor prognosis despite low MELD scores -> MELD Na • Patients must be referred to liver transplant center BEFORE factors associated with poor prognosis become evident: • - ascites with low (< 130 mEq/L) serum sodium • - ascites with marked sodium retention (u-Na < 10 mEq/day) • - ascites with decreased creatinine clearance • - low arterial pressure • - high C-P/MELD score (15 points) Cárdenas A et al. Clin Gastroenterol Hepatol. 2005 Senousy BE et al. World J Gastroenterol. 2009

  16. REFRACTORY ASCITES • Take home messages • Refractory ascites • Confirm diagnosis: • NSAIDs, ACE-I • Infections • Compliance to diet • Start treatment • Repeated LVP plus albumin • TIPS insertion • (Long-term albumin infusion?) • (Alfapump?) • Definitive treatment: OLT

  17. Renal Failure Prognosis 1) 3) 4) 2) Treatment strategies Definition Diagnostic criteria

  18. Diagnostic Criteria Prognosis Definition Treatment strategies Acute Kidney Injury (AKI) • TYPES OF AKI • Prerenal (27-50%) • Intrarenal – acute tubular necrosis (ATN) (14-35%) • Post-renal - rare • HRS(15-43%) -> specific type of AKI which develops in cirrhotic patients • Gines P et al. Nat Rev Dis Primers 2018 Portfolio Presentation

  19. Pathogenesis V. Arroyo et al. Hepatology, 23 (1996)

  20. HRS (OLD DEFINITION) • SCr value ≥1.5 mg/dl (index of GFR ≤ 40 ml/min) • HRS type I • HRS type II • OBSOLETE DEFINITION • Does not take into account changes in SCr with respect to baseline values (AKI or CKD?) • Patients with SCr > 1.5 already have marked GFR reduction Adaptation of Kidney Disease Improving Global Outcomes (KDIGO) definition of Kidney Injury in the setting of cirrhosis Arroyo V et al. International Ascites Club. Hepatology 2007

  21. Diagnostic Criteria Prognosis Definition Treatment strategies • New concepts in definitions of renal impairment: • HRS: phenotype of renal dysfunction that occurs in patients with cirrhosis and ascites. • Different underlying renal dysfunctions: • - acute (AKI), • - sub-acute (AKD) • - chronic (CKD)

  22. Diagnostic Criteria Prognosis Definition Treatment strategies • International Club of Ascites (ICA) / Kidney Disease Improving Global Outcomes (KDIGO) guidelines – new AKI definition: • Increase in sCr by ≥0.3 mg/dl (≥26.5 μmol/L) within 48 h; or • Increase in sCr to ≥1.5x baseline* within the prior 7 days; or • Urine volume <0.5 ml/kg/h for 6 h irrespective of SCr variation (Amathieu et al. Hepatology 2017) * SCr obtained in the previous 3 months • Angeli P et al. J Hepatol. 2019 • The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  23. DiagnosticCriteria Prognosis Treatment strategies Definition 5 year survival: 0% • 90-day survival: • Stage 1 AKI: 70% survival • Stage 2 AKI: 48% survival • Stage 3 AKI: 43% survival Angeli P et al. J Hepatol. 2019 • Huelin P et al. Clin Gastroenterol Hepatol 2017

  24. DiagnosticCriteria Prognosis Definition Treatment strategies • Angeli P et al. J Hepatol. 2019 • The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  25. DiagnosticCriteria Prognosis Definition Treatment strategies • Differential diagnosis • Is it pre-renal (vomiting, diarrhea, diuretics)? – adequate volume expansion, diuretic withdrawal • Is it nefrotoxic (NSAIDs, aminoglycosides, iodinated contrast medium)? – medical history • Is it a parenchymal disease? – Urine biochemistry, renal ultrasonography • Is it acute tubular necrosis (ATN)? – Tubular injury markers • - FeNa (fractional excretion of sodium) evaluation: • ATN: FENa > 2-3% due to tubular injury which limits sodium reabsorption • HRS: FENa < 0.2% • Other markers: NGAL, IL-18, KIM-1, L-FABP Angeli P et al. J Hepatol. 2019 The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  26. NGAL Neutrophil Gelatinase-Associated Lipocalin • Glycoprotein secreted by neutrophils, macrophages, epithelial cells (renal tubular cells) • Increased levels in case of tubular damage • Promising biomarker to discriminate between ATN and HRS-AKI • ATN-AKI: NGAL > 220 ug/g of creatinine (86% of ATN patients) • HRS-AKI: NGAL < 220 ug/g of creatinine(88% of HRS-AKI) Belcher JM et al. Am J Kidney Dis 2011 Huelin P et al. Hepatology 2019

  27. DiagnosticCriteria Prognosis Definition Treatment strategies Treatment The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  28. DiagnosticCriteria Treatment strategies Prognosis Definition Medical Treatment • 1) Terlipressin (counteracts splanchnic vasodilation) + Albumin (increases effective volume and cardiac contractility + anti-inflammatory effect) • The combination is more effective than albumin alone (Sanyal AJ et al. Aliment Pharmacol Ther 2017) • Significant improvement in renal function and better survival rates (Facciorusso A et al. Lancet Gastroenterol Hepatol 2017) • Terlipressin in iv continuous infusion: fewer side-effects (Cavallin M et al. Hepatology 2016) • 2) Noradrenaline + Albumin • Contrasting results on efficacy – Terlipressin better than Noradrenaline in ACLF?(Arora V et al. Hepatology 2018) • Cheaper than Terlipressin • Requires central venous line • 3) Midodrine + Octreotide + Albumin • Less effective than Terlipressin The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  29. DiagnosticCriteria Prognosis Definition Treatment strategies • How long? • Continue treatment until sCr within 0.3 mg of the patient’s baseline sCr • If no response/partial response: continue until 14 days • ~ 50% (20.0% - 80.4%)of nonresponders to Terlipressin in RCTs • Angeli P et al. J Hepatol. 2019 The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  30. DiagnosticCriteria Prognosis Definition Treatment strategies Why no response? • Vasoconstrictors • Type: terlipressin vs others • Modalities and duration of administration: terlipressin continuous iv infusion starting 2 mg/day. If SCr decrease < 25% at 48h -> increase up to 12 mg/day. • Stop if: • Complete response • Partial or no-response after 14 days of treatment • (Cavallin M et al. Hepatology 2015) Angeli P et al. J Hepatol. 2019 The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  31. DiagnosticCriteria Prognosis Definition Treatment strategies Why no response? Role of albumin • Salerno F et al. 2015 • Correlation between cumulative dose of • administrated albumin and 5-month survival • Fernandez J et al. 2019 • Correlation between high albumin doses (1.5 g/kg/week) and systemic inflammation Fernandez J Gastroenterology 2019 Salerno F et al. BMC Gastroenterol 2015

  32. DiagnosticCriteria Prognosis Definition Treatment strategies Why no response? • Elevated baseline SCr:negatively correlates with response • Is there a structural damage? • High number of organ failures in ACLF = lower response: ROLE OF INFLAMMATION Angeli P et al. J Hepatol. 2019 The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  33. IS HRS-AKI JUST A FUNCTIONAL DISEASE? Acute tubular interstitial injury/glomerular injury despite absence of proteinuria or haematuria Trawalé JM et al. RENAL HISTOLOGICAL FINDINGS in cirrhotic patients with renal impairment Belcher JM et al. NGAL as urinary biomarker of tubular damage/ATN in cirrhotic patients with renal impairment NGAL and other biomarkers indicative of structural damage are elevated in both patients with ATN and HRS

  34. New pathogenetic insights in HRS-AKI • Role of circulatory disfunction • Role of systemic inflammation Pathogen associated molecular patterns (PAMPs) released due to increased bacterial translocation Damage associated molecular patterns (DAMPs) released by damaged hepatocytes Release of pro-inflammatory cytokines (TNFa, IL-6, IL-1b) • KIDNEY DAMAGE • ACUTE LIVER FAILURE • ACUTE-ON-CHRONIC LIVER FAILURE • Angeli P et al. J Hepatol. 2019 • Sole C et al. Liver Int 2019 • Piano S et al. Clin Gastroenerol Hepatol 2018

  35. Role of inflammation in HRS-AKI development

  36. DiagnosticCriteria Prognosis Definition Treatment strategies Which other options? • TIPS (selected patients with relatively preserved liver function) • Renal Replacement Therapy (RRT) • Patients with unresponsive HRS-AKI who are candidates for LT • Severe electrolyte and/or acid-base imbalance • Oliguria with volume overload (diuretic resistance/intolerance) • Consider individual severity of illness (futility?) • Molecular adsorbents recirculating system (MARS) • Fractionated plasma separation and adsorption (FPSA- Prometheus) RATIONALE: Removal of endogenous vasodilators, bacterial products and inflammatory cytokines responsible for HRS-AKI. • Limited data available, inconclusive results. Angeli P et al. J Hepatol. 2019 The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  37. DiagnosticCriteria Prognosis Definition Treatment strategies Which other options? • OLT • Best option in patients with HRS regardless of response to drug therapy • HRS before LT has relatively negative impact on survival (Boyer TD et al. Liver Transpl 2011) • 5-year survival 60-70% versus 0% in HRS non OLT • 70-80% SURVIVAL IN NON HRS NON OLT (Low G. et al. Gastroenterol Res Pract 2015) The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018)

  38. HRS-AKI Take home messages HRS-AKI New definition: focus on small creatinine changes (SCr > 0.3 mg/dL from baseline) Confirm diagnosis: • Prerenal? • Nephrotoxic? • Parenchymal? • ATN? • Vasoconstrictors + Albumin NO RESPONSE? • Correct vasocontrictor • Adequate albumin dosage • Elevated SCr • ACLF • (Other treatments?) • Definitive treatment: OLT

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