In clinical trials of renal transplantation, we often take surrogate markers for graft survival such as rejection rates, serum creatinine and GFR as primary endpoints. In liver transplantation, it is less clear which outcomes are most useful and predictive of graft survival. Suggested biochemical markers include peak AST in the week following surgery, or composites such as Early Allograft Dysfunction (EAD, a combination of peak AST, INR and bilirubin).
Is there any evidence to suggest which surrogate performs best in liver transplantation?
On another note, there is some evidence to suggest that the outcomes that researchers and clinicians think are important to measure in clinical trials are not always the same as those that patients see as important (see attached paper). Is anyone aware of any similar publications regarding patient perspectives on outcomes following liver transplantation?
Article Important Outcomes for Kidney Transplant Recipients: A Nomin...
In this era of Value Based Care, one important measure that takes many clinical and social issues into consideration is the overall cost for the first year of care. This should include pre-transplant costs from listing as another metric. This will take into account decision to list, management on the waiting list, surgical care, medical care, immunosuppression regimen costs, readmissions and costs of managing complications. These should then be risk stratified and combined with standard survival outcomes for a composite score.
Clearly other important metrics you refer to, such as eGFR, HCC recurrence rates, etc. are also important. The problem is that the FDA and industry want short term measures. If you look at our H2304 Everolimus in liver transplant study, the impressive retention of renal function as measured by eGFR up to 4 years should be enough incentive to move to a lower dose tacrolimus with everolimus immunosuppressive regimen.
Rejection is assessed clinically through monitoring of liver function tests, and histopathologically by biopsy. Demetris AJ, Ruppert K, Dvorchik I, Jain A, Minervini M, Nalesnik MA, Randhawa P, Wu T, Zeevi A, Abu-Elmagd K, Eghtesad B, Fontes P, Cacciarelli T, Marsh W, Geller D, Fung JJ: Real-time monitoring of acute liver-allograft rejection using the Banff schema. Transplantation. 2002 Nov 15;74(9):1290-6.
Interesting question. In Howell et al. only 12% of participants ranked their own survival as more important than transplant ( I am assuming graft) survival. Return to dialysis is an option with more of a safety net than guaranteed re-transplantation. John Fung provides a thoughtful response re first year cost.
I would argue the measure should be return to productive lifestyles. Return to work is the most commonly used metric, however we know that not only are many recipients are at retirement age, financially can retire early, or were never in the workforce. there are many other productive social roles we can measure.
We have clearly identified person and graft survival rates. The costs in the first year are likely the highest, the degree to which the person gives back to society, in paying for the success of this transplant over 10+ years is likely a better metric.
A so called balanced suite of measures in my opnion would perhaps provide the best measure of outcomes. Freedom from ongoing complications (which would need to be defined) could be used as a metric. Patients can be alive at one year but having to return to hospital regularly for the management of problems eg biliary stenoses, recurrent infection. This measure could then be combined with graft survival, cost and some kind of measure of patient satisfaction (or quality of life) perhaps.
I agree a combination of health status ans PRO outcomes are relevant. We are at the point however that we need to look at factors other than satisfaction with health care. The use of patient satisfaction is problematic in liver transplantation as the alternative is death. Yes, patients have the right to be treated in a way that they find satisfactory, and we need to provide the best treatment possible, at the same time patients need to take responsibility for becoming active responsible citizens.
The most common complications of liver transplantation are:
The bleeding incomplete surgical hemostasis, coagulation disorders
-imunohemolitičke complications due to ABO incompatibility
Violation of the right phrenic nerve
-tromboza Hepatics artery and vein with disfunkcijiom veins Cava
-stenoza the anastomosing veins of Cava
-stenoza or dehiscence of the bile ducts
-non specific cholestatic syndrome, organ rejection, bacterial infection and sepsis, viral infections
-isolated or associated with other drugs toxic effects of cyclosporine in the liver, CNS, kidneys and other systems
DATA error cause complication in 10% of adults and 30% of children in transplantation. Each of these complications is very serious and the treatment is very complex with the engagement of the entire transplant team!
Immunological bases liver transplantation:
Despite steady progress in the Experimental and clinical field of knowledge or understanding of the mechanism in accepting the transplanted organs and tissues transpntacije liver remains a complex medical problem! Transplantation of any kind of tissue, not to be considered, a simple replacement of damaged tissue functions the same specific organ or tissue!
Especially in the case of liver transplantation should be talking about the interactions between the immune system and the immune system graft domaćina.Imuni response is divided into antigen-specific and non-specific response to antigen-specific response, known as the adaptive immune system, is dictated by the specific receptors on antigen that bonded to T and Blimfocite!
Non-specific immune system, known as internal immune system is characterized by immune effector cells that have antigen specific receptore.Ove cells including macrophages, natural killer cells, polymorphonuclear leukocytes and kompplement system.
The key component in the regulation of antigen specifičnog- system and non-specific immunity in liver transplantation are solibilni mediators known as cytokines!
Today, the liver graft rejection to date of origin, histological characteristics and reversibility classified in hyperacute, acute and chronic!
Hyperacute transplant rejection
This is neuobičajan event in liver transplantation, with a small number of cases reported in the literature! Takes place within a few seconds to a few hours after the transplant (from the revascularization of the graft).
It is characterized by rapid graft dysfunction, often with symptoms and signs of acute liver failure! Usually the patient is febrile with pain under the right rib cage, with elevated liver enzymes, bilirubin, thrombocytopenia and disturbances in acid-base status?
Hyperacute rejection triggered by antibodies and complement, which frequently targeted to the vascular endotel.Antitijela leading to hyperacute rejection syndrome are either preformed HLA -antitijela against donorovih MHC antigen, or refer the anti-blood group antigens.
Characteristic pathological findings of a massive haemorrhagic necrosis associated with complement, fibrin and immunoglobulin deposits in the arteries, veins and sinossoidima! There may be a segmental infarction graft together with necrosis, bilijatrnog tract.
Treatment is difficult and the use of plasmapheresis, cyclophosphamide and OKT3 gives poor results .
Only relatively effective treatment is the urgent retransplantation!
Acute Liver transplant rejection
Acute liver graft rejection occurs in 60-70% of patients, and there is from the first to the fourth week after liver transplantation! The initial process takes place in the microvasculature grafta.Microvasculatura has a narrow lumen and greater eksresiju MHC molecules and other adhesion molecules!
This predisposes the combination of an interaction between leukocytes and endothelium. Predominant cell type that participates in the acute rejection of the T cell and molecular mechanism involves the reaction of delayed reactions with tissue macrophage activation and cytokine production.
There may be no clear clinical symptoms or the occasional inconvenience under the right rib arch, and fever, and elevated bilirubin, alkaline phosphatase and liver enzymes.
The diagnosis of acute rejection of liver raises liver biopsy and is defined as inflammation of the liver allograft genetic disparity between donor and recipjenta, and primarily affects the vascular endothelium., Drawn down and the portal vein and hepatic tubules, and occasionally hepatic artery and its branches, as well as interlobarni bile lines.
Therefore, we have predominantly three histopathological image: portal inflammation, damage to the bile ducts and endotelitis.Najmanje two of these three characteristics are necessary in order to give a histopathological diagnosis of diseases acute rejection!
Chronic rejection of liver transplants
Chronic liver transplant rejection occurs at less than 10% of patients in the period of 3-6 months after transplantacion .There several predisposing factors for chronic rejection, delayed episodes of liver transplant, such as low levels of cyclosporine, multiple episodes of acute rejection, delayed episodes of acute rejection , CMV infection, positive limfotoksična antibodies, HCV infection and gender differences between the recipient and the donor!
Chronic rejection is followed by a progressive cholestasis with all its clinical and biochemical characteristics.
The diagnosis was based on histology of liver and to characterize the two predominant lesion. The first is the loss of interlobar bile ducts so-called "vanishing bile duct syndrome" .He is associated with the loss of the microvasculature and arteriolar structure within in the portal tract and reducing more often than an increase in inflammatory infiltrate.
Portal tract often remain small and fibrous.
The other major change occurs hepatic lobules with progressive ballooning in zone three hepatic lobule and Liver necrosis.
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