Post Living Donor Liver Transplantation Small for-size Syndrome

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1. Post Living Donor Liver Transplantation Small for-size Syndrome Guidelines From the ILTS – iLDLT - LTSI Consensus Conference Ho Nam. MD Surgical and Transplant ICU 108 Military Central Hospital Diagnosis and Management

2. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Introduction LDLT has become the treatment of choice for patients with end-stage liver disease, especially in regions with limited options for deceased donor liver transplantation. G raft dysfunction associated with small graft size remains a major concern In 1996, Emond described the clinical course after a small-for-size transplant as being characterized by significant functional impairment associated with paradoxical histologic changes typical of ischemia. The concept of SFSS began to emerge , wherein a clinical manifestation of graft insufficiency post-LDLT was characterized by persistent cholestasis, increased ascites, and coagulopathy.

3. TRANSPLANTATION OF THE LIVER Third Edition, Ronald W. Busuttil, MD, PhD 2015 Introduction

4. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Introduction SMALL FOR-SIZE SYNDROME

5. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 1: What is the Definition of SFSS After LDLT? Recommendationsç SFSS is a clinical syndrome caused by a partial liver graft that is too small to fulfill the metabolic demand of the recipient in the absence of specific surgical or nonsurgical causes. High S trong Grade of evidence Grade of recommendation Definition SFSS

6. TRANSPLANTATION OF THE LIVER Third Edition, Ronald W. Busuttil, MD, PhD 2015 Definition SFSS

7. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Questions 2: What is the Ideal GRWR (or Graft Volume to Standard Liver Volume)? Definition SFSS

8. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Questions 2: What is the Ideal GRWR (or Graft Volume to Standard Liver Volume)? Recommendationsç The ideal GRWR should be ≥0.8%, and GV/ SLV ratio should be ≥40% to prevent SFSS High S trong GRWR as low as 0.6% or GV/SLV ≥30% can be considered in the setting of portal inflow modulation and reserved for recipients with low MELD scores or no significant portal hypertension Moderate Low Grade of evidence Grade of recommendation Definition SFSS

9. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 3: What is the Appropriate Level of Postreperfusion Portal Pressure and Flow? Definition SFSS

10. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 3: What is the Appropriate Level of Postreperfusion Portal Pressure and Flow? Definition SFSS Recommendationsç Portal pressure and/or flow measurement should be included as one of the standard measurements. Portal pressure postreperfusion be maintained at <15 mmHg or portal flow of <250mL/min/100g graft weight is recommended to prevent SFSS Moderate S trong Grade of evidence Grade of recommendation

11. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 4: What is the Best Time Point to Define SFSS? Timeline of Diagnosis

12. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 4: What is the Best Time Point to Define SFSS? Timeline of Diagnosis Recommendations The typical time point to make the diagnosis of SFSS is postoperative day 7 to facilitate the treatment plan . SFSS may manifest after the second week with features of cholestasis and portal hypertension. Moderate Moderate Grade of evidence Grade of recommendation Li ver biopsy: hepatocyte ballooning, arteriolar thrombosis, portal endothelial damage, and cholestasis between day 7 and 20. S ome of these features can be observed as early as day 3 in severe cases. It is important that portal hyperperfusion and SFSS be diagnosed early to allow interventions before the development of clinical signs of graft failure

13. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 5: Is a Dynamic Evaluation More Appropriate? Timeline of Diagnosis Recommendations Dynamic evaluation of clinical and biochemical factors between time points can be of benefit in defining SFSS and prognosticating outcomes. Moderate Strong Grade of evidence Grade of recommendation SFSS is a dynamic process ; impacted by concurrent processes of ongoing graft injury and regeneration. D efinitions of SFSS depend on single cutoffs of laboratory variables at specific time points. Serial measurements of biochemical and clinical factors and changes in these values may provide a more accurate definition of SFSS and improve prognostication of established SFSS

14. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 T otal bilirubin, INR and massive ascites being a specific clinical factor for the definition of SFSS. Preexisting hyperbilirubinemia or ascites before transplantation should be taken into account when diagnosing SFSS if conditions do not improve. In predictive model development for SFSS, additional factors such as elevated serum urea and thrombocytopenia are supportive but still warrant further evaluation Biochemical and Clinical Factors Necessary for Diagnosis

15. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 6: Does Histology Need to be Included in the Definition of SFSS? Biochemical and Clinical Factors Necessary for Diagnosis Recommendations In the presence of sufficient biochemical and clinical evidence of SFSS, histological features are useful but are not required for diagnosis Low Strong Grade of evidence Grade of recommendation

16. Post Living Donor Liver Transplantation Small- for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Transplantation 2023 Question 7: Can SFSS be Categorized Based On Severity? Grading the Severity of SFSS Recommendations SFSS after LDLT can be categorized into 3 groups, including “ grade A, pre-SFSS”; “grade B, portal hypertensive phase SFSS”; and “grade C, liver failure phase SFSS .” Validity of this newly created severity criteria should be evaluated or confirmed in future (prospective) studies. Moderate Moderate Grade of evidence Grade of recommendation

17. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Management

18. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Pharmacological agents to reduce portal flow/pressure

19. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Pharmacological agents to reduce portal flow/pressure Recommendations A1. Pharmacological Interventions for Management of Established SFSS Early intervention with SST (octreotide) might be considered to decrease PVP in patients with SFSS Moderate Moderate PGE1 and beta-blockade may also be considered to improve SFSS Low Weak A2. Standardized Protocol of Pharmacological Interventions for Management of Established SFSS Adequate trough levels of immunosuppressive medications should be maintained in the setting of SFSS Moderate Strong Grade of evidence Grade of recommendation

20. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Supportive Care S upportive care to optimize graft regeneration and recovery including P revention of rejection P ain management I nfectious prophylaxis M anagement of ascites F luid balance.

21. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Supportive Care : P revention of rejection and P ain management LDLT recipients require smaller doses of tacrolimus , process of liver regeneration may impact the hepatic metabolism thus affecting tacrolimus serum levels. Kishino : donor age and smaller graft volume to standard liver volume were associated with prolonged half-life of tacrolimus. Liu: tacrolimus dosage was lower for 2 mo in the LDLT group with GRWR <0.8% compared GRWR ≥0.8%. O pioid and other sedative undergo hepatic metabolism, opiates should be used judiciously to avoid adverse events.

22. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Supportive Care: I nfectious prophylaxis Currently, no data are available on antibiotic prophylaxis in the setting of SFSS T hus it would be reasonable to follow established postoperative recommendations on use of antibiotics in liver recipients. In the setting of hyperammonemia, administration of rifaximin may be considered

23. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Supportive Care: M anagement of ascites Ascites management is one of the key aspects in patients with SFSS T here are no data available on standardized practice. A pproach should be similar to the pretransplant setting focused on: M oderate volume of ascites: Di uretics and sodium restriction L arge volume: paracentesis followed by plasma expansion would be appropriate for large volume or refractory ascites Replacing the volume loss with 5% albumin prevents the hypovolemia and renal dysfunction

24. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Medical Management Of SFSS Extracorporeal Support Continuous renal replacement therapy Molecular adsorbent recirculating system Plasmapheresis Reduce toxins but do not replace synthetic and metabolic hepatic functions

25. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical Interventional Radiology a nd Surgical Management Of SFSS When pharmacological portal flow modulators fail in grade B (portal hypertensive phase of SFSS) or severity of the condition progresses to grade C (impending liver failure), IR/surgical techniques to reduce portal overperfusion via graft inflow modulation (GIM) are recommended

26. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical Interventional Radiology: I R Techniques (SAE, Splenic Embolization) in the Postoperative Setting Recommendations Proximal versus distal embolization of the splenic artery can be effective to mitigate Grade B SFSS (portal hypertensive phase). Low Moderate Grade of evidence Grade of recommendation

27. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical The Indications and Techniques for Surgical Interventions in the Postoperative Setting Recommendations Surgical intervention can be beneficial to those with Grade B SFSS (portal hypertensive phase) that have failed to respond to medical therapy and IR techniques Low Moderate Splenic artery ligation (SAL) /splenectomy is beneficial and recommended as surgical treatment choice in posttransplant Grade B SFSS cases that fail IR interventions Low Moderate Grade of evidence Grade of recommendation

28. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical The Best Modality for Evaluation of Response to Treatment in SFSS Recommendations We suggest the use of the following factors to evaluate the response to treatment in SFSS: recovery of liver function (tests), decrease in ascites, and improvement of urine output/renal function Low Moderate Grade of evidence Grade of recommendation

29. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical Retransplantation For SFSS: Criteria for Retransplantation Recommendations When medical/IR/surgical interventions fail in SFSS, re-LT should be considered. The decision to retransplant should be based upon the overall clinical situation considering persistent hyperbilirubinemia (total bilirubin >10mg/dL) with coagulopathy (INR >1.6) or isolated hyperbilirubinemia (>20mg/dL); ascites; rising ammonia; dysfunction of other organs and absence of sepsis. Low Moderate Grade of evidence Grade of recommendation

30. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical Retransplantation For SFSS: Timing of Retransplantation Recommendations Based upon the relatively good outcome for patients with segmental graft dysfunction/SFSS, it might be reasonable to avoid re-LT in the first 2wk to allow for graft regeneration and/or recovery, except in the situation of Grade C SFSS in which re-LT is recommended given the significant risk of graft failure. Low Moderate Grade of evidence Grade of recommendation

31. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference Interventional Radiology a nd Surgical Retransplantation For SFSS: Retransplantation Futility Recommendations Criteria for the futility of re-LT in SFSS following LDLT may be similar for re-LT for other indications. Moderate Moderate Re-LT should be proposed with caution in patients with concomitant significant renal dysfunction and increasing pressor requirements and avoided in patients with ongoing sepsis or untreated infection (especially with multidrug resistant organisms) Moderate Moderate Grade of evidence Grade of recommendation

32. Management of Established Small-for- size Syndrome in Post Living Donor Liver Transplantation: Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS- iLDLT -LTSI Consensus Conference TAKE-HOME MESSAGE SFSS: lead to devastating outcomes, prolonged poor graft function and graft loss. Portal hyperperfusion of a small graft and hyperdynamic splanchnic circulation are recognized as main pathogenic factors . Management is guided by the severity of the presentation with the initial focus on pharmacological therapy to modulate portal flow and provide supportive care When medical management fails or condition progresses: IR and/or surgical interventions Retransplantation should be considered based on the overall clinical situation and the above postoperative laboratory parameters.

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