Strategies to Improve Long Term Dutcomes of Kidney Transplantation
In this presentation, Dr. Abhijit Konur, a senior consultant nephrologist at Kidney Hospital, Nariya, Gujarat, focuses on short-term and long-term kidney transplant outcomes, strategies to improve them, and the role of thymoglobulin in enhancing long-term success.
Key Points:
- Kidney transplantation significantly improves survival, quality of life, and reduces dialysis dependency.
- Long-term outcomes remain a challenge due to immunosuppression-related complications, infections, cardiovascular diseases, and chronic rejections.
- Strategies to enhance outcomes include donor selection, pre- and post-transplant interventions, immunosuppressive regimens, and monitoring strategies.
- Thymoglobulin plays a crucial role in preventing acute rejection, improving graft survival, and is beneficial in high-risk transplants, including ABO-incompatible cases.
Despite advancements, challenges persist, necessitating optimized immunosuppression and tailored interventions for better patient and graft survival.
Dr. Abhijit Konur
Good day everybody. I am Dr. Abhijit Konur. I am a senior consultant nephrologist at the kidney hospital in Nariya in Gujarat and a very happy kidney work kidney date to you very in advance. And today let me thank Tanofi for giving me this opportunity to speak on this very important and intriguing topic for all nephrologists, young and old experienced and inexperienced alike. It is strategies to improve long-term outcomes of kidney transplant. So, a fairly long discussion at soil start off without wasting any more time. So, there is a disclaimer. The discussion is meant for physicians to update strategies to improve the outcomes of kidney transplant and is meant only for educational purposes. It is possible that some information on specific drugs is out of approved level and Sanofi is not responsible for the off-label use of their labs and physicians are requested to refer to the full prescribing information before prescribing any product. So, the learning objectives of today's presentation is to understand the short-term and long-term outcomes of kidney transplant, to understand the modalities of to improve the short-term and long-term outcomes and to understand the role of time of global in improving long-term outcomes of kidney transplantation. It will be in three sections and this first section is kidney transplant and beyond. What are the potential benefits outcomes of kidney transplantation? It is supposed to be the optimal treatment for patients with end-stage kidney disease because it improves the survival and quality of life, reduces the need for dialysis and reduces dietary restrictions. So, as we all know, there has been a rise in kidney transplant patients experiencing the side effects and complications of chronic immunosuppression and the long-term kidney or alograft outcome remains unchanged. So, as we see in this cartoon, the initial 3-12 months after the transplant is designed that the right acute rejections and late acute rejections, drug-related toxicities, BKV nephropathy, veteran disease and urinary infections, which influence the early outcomes of a transplant. But later on, long-term outcomes are defined by the incidences of rejections, infections, cancers, recurrent kidney disease and cardiovascular disease. So, non-emulological complications play an important role in the long-term, alograft and patient survival. The prevalence of kidney transplant outcomes are influenced by one presence of acute rejections. Incidents decrease with the use of more potential immunosuppressants, but still 10% receive grants and develop acute rejection within the first year. Second is presence of infection, which is the second leading cause of death associated with decreased graft survival. And the incidence of infection within one month is anywhere from 10% to increased incidences of 68% within the first six months. Where 6% are bacterial, viral form 3.8% and fungal 2.1%. The third is cancer, one is one of the major causes of death and the standardized incidence ratio of cancer in kidney transplant recipient is in the range of 1.11 to around 30%. And lastly, most importantly, is cardiovascular disease, which forms the leading cause of death and the prevalence of cardiovascular disease ranges anywhere from 40 to 90% in hypertenors around 20 to 40% in diabetics and 50% dysrecchial equation. In Indian scenario, there are two studies which have studied this. One is a Sharma et al which showed that graft dysfunction was the most common cause of preadmission within 30 days of discharge followed by unit rank infection, which is around 16% and Dr. Banoda study in 2021, which showed that transplant outcomes after 5 years, there is 70% risk on death due to infections and 30% due to cardiovascular outcomes. So if you look at the cartoon on the left, one can see that at one year, the graft survival is anywhere at 89% and patient survival is 90%. At 5 year, the graft survival decreased by around 5 to 6% where patient survival is 81%. And the long term graft outcomes that we are going to discuss ahead one around 65% had normal functioning graft after 5 years. Most of the causes of graft dysfunction where due to death or graft loss due to rejection, run it, grab dysfunction due to rejections, if that and the occurrence of native disease. Hence, there is a need for better care. Despite improved outcomes due to better perioperative care, annual rates of graft failure beyond 5 years post-transplant have remained unchanged since the 1990s. And inadequate or ineffective immunosuppression remains a major cause of early as well as late graft failure. So there is a need for better and more consistent care with newer therapeutic modalities. Important slide because it defines the interventions affecting long term graft survival. So one could be donor-related interventions, organ-related interventions and finally recipient-related interventions. So the donor-related intervention is one is promotion of live donor kidney transplants. As we all know, live donors do much better than disease donors. There is promotion of living donor paired exchanges wherever it's possible. Judicious use of kidneys with high KDPI, use of patients, extended criteria donors where one may have HCV and HIV as the disease donor kidneys, where therapies for these modalities are now available. These are all strategies to improve and increase the patient, the organ pool. And last is testing for a Paul van Risk LLC, especially in bad donor and recipients. In organ-related interventions, the quality of the donated organ is very important. So living donors definitely do better than deceased. Second is SLM-HLA matching or mismatch. Delave graft function and donor age, the difference between donor and recipient is also present for control. Presence of preexisting HLA antibodies is definitely a bad hair pincher for kidney transplant and recipient-related interventions like early referral and a plant kidney transplantation, preemptive kidney transplantation, a management of home morbidities like hypertension, diabetes, dystipidemia, and obesity and preparing the patient well for a transplant surgery, rehabilitation, immunization, cancer surveillance and really select patient selection so that no patient who has significant vulnerabilities or limited lifespan ahead should be transplanted, especially in the era of where there is organ shortage. Pre-transplant interventions which can influence outcomes, one is serologic HLA testing, HLA DR matching and effluent scoring, and use of virtual cross-matching, I think are done in most of the major sectors, including mine here in Mojavei Patele kidney hospital, which helps us improve the outcomes both short-term and long-term in patients with two undergoing kidney transplant. Post-transplant interventions are extremely important, adequate and appropriate level of immunosuppressive agents, use of surveillance biopsies, early detection and treatment of rejections, need, T-cell mediated or antibody mediated, using non-CNI strategies like balata-cep in certain patients. Biomarker use a diagnosis of an early rejection, infections, surveillance and early detection, especially BK virus and cytomegalic virus screening, and diagnosis and management of post-transplant lymphoma proliferative disease, early detection of native kidney disease, especially recurrence of low on arthritis, and cancer screening for long way in giving a long outcome to a kidney transplant program, and also individually improving the graft survival in patients with post-kidney transplant. A few rejections are always a cause of concern, it is an important cause of death-sensored graft loss, it can occur anywhere from 2 to 6 weeks, it can occur from 3 days to 10 years after a kidney transplant, and as we all know it can be of broadly true types, although sometimes it's very difficult to separate one from the other, one is a cell mediated acute rejection, which is typically seen within one week after a kidney transplant, usually mediated by T-cell reacting to donor histocompatibility in patients, and it's usually more common, and antibody or humeral rejection is mediated by donor specific antibodies, and is increasingly being recognized as a cause of chronic antibody-mediated rejection, and the rejections are treated by IV steroids or leukocyte-depleting strategies, still 10% of recipients develop acute rejection within first year. Despite use of potent immunosuppressivity like C and I's, the risk has decreased but not negated, and these are associated with high incidences of infections because of excessive immunosuppression and complication. The problem of chronic rejection, this occurs despite reduction in acute rejection, and the cause could be due to chronic antigen-specific cellular mechanisms and humeral immune mechanisms. Unfortunately, there is no current specific strategy aimed at influencing or treating these chronic rejections. There are a host of reasons why this may occur as was it is seen on the right side cartoon, where immunologic factors like poor HLA matching and delayed graph function leads to episodes of acute rejection, and non-compliant on part of patients, especially teenage patients, and suboptimal immunosuppression leads to subacute and chronic LO immune response, all leading to chronic alograft nephropathy. Non-immunologic factors like older donors, poor graph quality, presence of brain death related injury, dysteomyaripar fusion injury, hypertension, hyperlepidemia, and toxic effects of the CNI, all lead to very transplantational injuries, delayed graph functions, and chronic alograft nephropathy. Antibody mediated rejection, antibody mediated rejection, and non-immunological contributions, complications following kidney transplant contribute to the failure of kidney alografts. Around 6.7% of kidney transplant recipients experience antibody mediated rejection, and 20-30% of patients with antibody mediated rejection experience graph loss within 1-2 years. So it's a serious matter, so anybody developing antibody mediated rejection, it's not good news at all, and treatment for the antibody mediated rejection, as we all know, is one is removal of antibodies using plasma terraces, plasma exchange, and adsorption columns, anti-me cell therapies, anti-plasma cell therapies, anti-te cell therapies, conversion to tacholimous waste, regimens, and terminal complement pathway inhibitors are all strategies designed to control antibody mediated rejection. T cell mediated rejection cause significant graph dysfunction, and there is concurrent presence of T cell mediated antibody mediated rejection in many of the graphs that are seen, and these usually occur in the first year in around 5-15% of patients, and some clinically have been seen up to 30% in early surveillance biopsies, and typically the treatment for acute T cell mediated grade 1 rejections are steroids, and grade 2 and above are steroids plus using anti-thimocyte don't be less. So in broadly, what are the current strategies at our disposal to prevent late-allegraph loss? One is pharmacologic prevention of acute rejection, improvement in perioperative management, treatment of severe or refractory acute rejections, discontinuation of steroids in patients in stable condition, a definition of optimal long-term dose of calcineurininifritors, treatment of comorbidities like hypertension and hyperlipidemia are some of the strategies that have been used. So let us discuss something about the induction therapies for effective transplant before we decide what how they influence long-term outcomes. The rational for induction therapy kidney transplant is to prevent acute rejection during early dose transplant period, and they should provide high degree of immunosuppression at the time of transplantation. Essential to demise outcomes, particularly in patients at high risk of who are short-term outcomes, especially those who are highly sensitized, and all the induction agents as we alluded to previously are biologic agents. And of this, the anti-thimocyte droplet, rabbit is the most common induction therapy, so popularly known as thymogromal. The choice of regimen depends on the preference of clinicians and comorbidities. The introduction of induction therapy has reduced the incidence of acute rejection post-transplant and he includes one-year survival. When kidney alograv outcomes for five years were compared between bacilli ximab versus lymph tissue map and thymoglobin used for induction, there was no difference, there was no difference to observe the time to first diagnosed rejection and severity of first diagnosis. It's a very important slide, this is something that all of us have been wondering. So in terms of probability of rejection, efficacy of these molecules probably are equally efficacious and we'll see some more data about this in the coming few slides. So choosing the induction agent, no induction to use of bacilli ximab, allentism map and thymoglobin. Anywhere where there is lower risk one would use no induction agent. So all those people who have zero HLA mismatch, life donors, complication, ethnicity, low PDRAs, blood group compatible, immediate graph function and first transplant fall in this category. Whereas higher risk are the ones who have more than 6-5-12 mismatches, differences in the donor recipient ages, African-American ethnicity, high panel reactive antibodies or presence of donor specific antibodies, blood group incompatibility, delayed graph functions, long cold simea time and a retransplant, all fall under the high risk category. The anti thymocyte globulin as we all know targets a wide range of T cells, surface antigens, induces a rapid and profound degradation of the CDT, deliposides in the blood and can be used to avoid steroid use and delay the use of calcium urine inhibitors, especially where delayed graph functions occur and without increasing the rejection rates. So all patients who are at risk that we are here alluded to could be used for an anoside program. In the Indian context kidney transplant is associated with a catastrophic out of pocket expenditure and total medical costs in the first year post-transplantar substantial and correlated with graft failure. Hence it's important to tailor these therapies to our patients where their reducer is of acute rejection, increase the graft and patient survival, decreasing costs and which induction of the two is better. So a RIMETATG gives a lower rate of acute rejection. Cost per patient anywhere is around from 69,000 rupees to 1.3 lakhs. The usual dose is 0.5 to 3 milligrams per kilogram. A very common question that upcoming to everybody's mind is between comparison between induction therapies like I add to receptor blockers like bacilxyenab and thymoglobin in kidney transplant. In angle center prospective double arm open label study, BABETATG was used as a single dose induction at 1.5 milligrams per day due on the day of transplant whereas bacilxyenab was used as 20 milligrams on day zero and day four. Incidents of acute rejection were slightly more in the bacilxyenab as compared to the low dose BABETATG arm and the cost of therapy was around $600 in the RABETATG as compared to bacilxyenab which was around $2,200. There was one case of pneumonia and one patient set up to coronary artery disease in the bacilxyenab arm versus no infection that were observed with the RABETATG and there was a 95% net sensor graft survival whereas there was no patient of graft drop in the RABETATG arm. So in a way RABETATG arm loaders was better option compared to bacilxyenab in terms of graft function survival and cost benefit in kidney transplant patients. Now specifically coming to the role of thymoglobin in improving long-term outcomes of kidney transplantation. Thymoglobin is used both in ABO in compatible kidney transplant and ABO compatible kidney transplant. Of relevance to all of us here many of us where we use a retoxymap and plasma pheresis as an induction therapy for ABO in compatible kidney transplants. Many of us are hesitant to use thymoglobin as one of the induction agents immediately perioperative. For the feeling that both B and B cell pathways will be blocked and may lead to increased infections. So in this particular study there in our country itself there was a include at both ABO in compatible kidney transplant and ABO compatible kidney transplant. This study was published in the Saudi Journal of Kidney Disease and Transplant Asian 2019 and was headed by Umar and Ray and all patients had received retoxymap and plasma pheresis and one year outcomes were compared. So patients survival in both the group was 96.6% and death sensor survival in both the groups was similar. The average serum-preyatin level EGF are incidence of rejection, effective episodes and post-transplant hospital stays were comparable. So ABO in compatible kidney transplant should similar outcomes as compared to competitors and it can be applied for more widely to meet the ever-increasing demand for organ donors and these are all in terms of short-term outcomes. A more broader long-term outcome study needs to be done in the future. Another controversial topic that we all face in our profession as kidney transplant physicians is comparing outcomes of thymoglobin with another counterpart called Grappalon as an induction agent in kidney transplant. Grappalon as we all know is chirpates are derived anti-lymphocyte deprecating agent and there are limited studies within and outside India which have compared these head-to-head as induction agents. In this study then under Dr. Kher et al in the Indian Journal of Technology 2021, a single-center retrospective study to compare these two. Grappalon was used at the dose of 6 mg per kg whereas thymo globally was used in the dose of 3 mg per kg and both followed similar standard immunosupparection that originates. As one can see that in the biopsy to an acute rejection rates were significant high in the patients who underwent transplant under the Grappalon now as compared to thymo globally. And patient survival was similar and death-sensored graft survival also similar in both these groups. So coming to a conclusion that there are significantly higher rates of prior cecuvant acute rejection with Grappalon although the short-term patient and death-sensored graft survival rates and the infection rates were comparable in both these apps. Comparison between i2 receptors and thymo globally and induction strategies in a view incompatible kidney transplant. This is something that as strategy that even I have myself used to where patients where we are hesitant to use thymo globally were in patients who have already been given retoxymab. But this slide actually gives us a very interesting insight into what are the outcomes that can be anticipated. So this was a study done by Devard and Beleri and published in clinical transplantation 2019 and it's a retrospective study to compare the outcomes of avian compatible type-tonal kidney transplant recipients where the polyclonal antibodies used were thymoglobin and Grappalon and the i2 receptor blockers and Grapp survival without acute rejection was studied according to the type of induction therapy. Now I asked all of you to just zone in on the cartoon and the graph on the right lower hand side. One thing was sure is that the use of i2 receptor blocker in the avian compatible therapy was definitely worse than in the one in the avian compatible therapy using i2 receptor blockers and also similar outcomes were seen in use of polyclonal antibodies. Therefore the rate of acute rejection was significantly higher in patients who were given iron 2 receptor blockers in the incompatible versus the compatible higher in the rabbit in the rabbit in the arm versus the in the basaltic-simab versus the rabbit in the flow graph function showed similar outcomes. Important at five years which we are so which we are dealing with today's topic is the five-year outcome in terms of triple end points that are five-square-an-accured rejection graph flaws and depth in the rabbit-atg arm that is the the rabbit-atg arm showed significant lower incidences as compared to the one in the basaltic-simab. Individually to acute rejection rates were lower in the rabbit-atg arm the presence of antibody treated acute rejection were lower and the CMV infection rates were also lower in the rabbit-atg arm as compared to the one with basaltic-simab. I would say here that there is a significant clinical difference in the indicating superiority of the rabbit-atg or pacific-simab. So rabbit-atg somehow has emerged as an alternative to i2 receptor antibodies in steroid-evident protocols. Although not very popular in our country the steroid avoidance of protocols when one is used even is studying i2 receptor antibodies rabbit-atg and lm chisumab as compared to no induction shows that rabbit-atg efficacious and significantly lower risk of acute rejections is seen in the rabbit-atg arm as compared to i2 receptor antibodies. The adjusted risk of acute rejection in rabbit-atg and lm chisumab was lower than i2 receptor so more potent without doubts as compared to i2 receptor antibodies. The significant difference between mortality rates between induction therapies this i think is a very important topic which must be underlined mortality at five years in the end one wants to see in the nose steroid arm the mortality rates were quite high in the i2 receptors as compared to the other two 6.1% versus 5.1 and 4.9% in the rabbit-atg and lm chisumab. In the steroid group the mortality rates were much higher in the non-adoption arm as compared to the induction arm and there was no significant difference between no induction and i2 receptor antibodies categories. So long-term efficacy of rabbit-atg versus bacilic sineap. By year clinical outcomes at five years very important and then 10 year clinical outcomes the benefits of induction with rabbit-atg in terms of acute rejection draft failure and death were sustained throughout the five-year post-transplant as compared to i2 receptors and at 10 years post-transplant rabbit-atg continued to have comparable efficacy in safety to bacilic sineap. I think the initial outcome for rabbit-atg is better as compared to i2 receptor antagonist over five-year periods that effect kind of telescopes to five years but at 10 years outcome they become comparable in terms of the clinical outcomes. So rabbit-atg versus bacilic sineap induction in living donor transplant long-term outcomes the safety and efficacy of low-dose rabbit-atg were comparable on a background of triple immunosuppressive maintenance therapy over the period of five years in this study by a palleta p again which was published in saucy journal of kidney transplant 2014 and if one goes to the survival rates most important patient survival and draft survival in these two groups as one can see are slightly different where in the rabbit-atg there is a higher patient and draft survival as compared to the one at the bacilic sineap. So both the induction primitive treatments offer a safe and effective treatment but were associated with excellent long-term patient and draft survival where rabbit-atg is seen to perform better as compared to i2 receptor antagonist. In comparison of lm2-zumab and bacilic sineap versus rabbit-atg lm2-zumab and rabbit-atg and bacilic sineap and rabbit-atg what are the differences there are higher risk of death associated with lm2-zumab so add the cd-3-3-3 antibodies to antibody lm2-zumab as we all know depletes both all the cell lines macrophages and natural killer cells and has a very potent immunosuppressive region probably leading to higher risk of death and a looked at failure with comparable outcomes in terms of rejections whereas bacilic back rabbit-atg there is higher risk of death in the bacilic sineap arm and higher risk of death or lymphoma with a hazard ratio of 1.12 in the bacilic sineap arm so primary outcome death and death of with graft failure and secondary outcomes usually studied are death sepsis death with lymphoma death due to myeloma compared to lm2-zumab and bacilic sineap rabbit-atg who is associated with lower risk of adverse outcomes including mortality and as a comparison between rabbit-atg and an old equine derived anti- thymocyte globulin also called ad-gam in this particular slide five-year freedom from acute rejections rabbit-atg performs much better than ad-gam and a freedom from acute rejection occurred in 92% of thymoglobin associate treated patients and 66% of ad-gam treated patients and five-year patient and graft survival also showed better outcomes in the thymoglobin group versus the ad-gam group so which is better on a head-to-head comparison even in efficacy-wide the lymphocyte subsets rabbit-atg seems to work better by depleting both CD3, CD4 and CD8 lymphocytes as compared to ad-gam and thymoglobin induction was associated with better even free survival at one year at five years it was associated with higher even when free survival and reduced long-term acute rejection rates without an associated risk of post-transplant lymphoid lymphopoly present disease and CMV disease in the thymoia and at two years there was profound lymphopenia in thymocrovaline group which may explain the long-term results so it depletes lymphocytes what it's supposed to do after transplant so coming to the blast and ultimate slide and key messages that we take home from this very important topic is that kidney transplants could have short-term as well as long-term complications such as infections acute rejection recurrence of primary kidney disease side effects of long-term use of immunosuppressants the annual rates of graft failure beyond five years post-transplant have been in unchanged over the period and there is a need for better and more consistent care antibody mediated rejection is significant and continued challenge for long-term graft survival in kidney transplants and anti-t cell therapies are potential therapies to manage this thymoglobin is an effective induction therapy its superiority with the respective efficacy and safety compared to other induction agents is well documented as we discussed in the previous slides and induction with thymoglobin is associated with better long-term outcomes such as patient and graft survival and low incidence of acute rejection thank you and it was an interesting topic and i thank you for giving it so much good day
