?For recipients of deceased donor kidney (SD, ECD, DCD) transplants, what is the comparative effectiveness of different induction agents (perioperative administration of an intensive immunosuppression agents: also called as…

Briefly describe a specific question, or set of related questions, about a health care test or treatment that this program should consider.

?For recipients of deceased donor kidney (SD, ECD, DCD) transplants, what is the comparative effectiveness of different induction agents (perioperative administration of an intensive immunosuppression agents: also called as immunoprophylaxis) to prevent the development of acute allograft rejection as well as delayed graft function? ?This question is particularly important in the current context of using combination of maintenance IS therapy consisting of tacrolimus and mycophenolate mofetil but without the use of maintenance prednisone therapy.

Does your question include a comparison of different health care approaches? (If no, your topic will still be considered.)

yes

If yes, explain the specific technologies, devices, drugs, or interventions you would like to see compared:

What is the comparative effectiveness of three different types of induction agents that are used in recipients of kidney transplants; a)Rabbit Antithymocyte globulin (thymoglobulin), b) Chimeric human-murine anti-CD 25 (Basiliximab), and, c) anti-CD52 antibody (Alentuzumab)?

What patients or group(s) of patients does your question apply to? (Please include specific details such as age range, gender, coexisting diagnoses, and indications for therapy.)

Any age group from year 18 to 80, men and women, diabetes mellitus, hypertension, chronic kidney disease without or with the need for dialysis therapy.

Are there subgroups of patients that your question might apply to? (For example, an ethnic group, stage or severity of a disease.)

Subgroups of patients would include recipients of different types of deceased donor kidneys (SD, ECD, DCD), diabetic vs non-diabetics, Caucasian vs. Hispanics vs African American, recipients with pre-emptive transplantation vs recipients on dialysis.

Describe the health-related benefits you are interested in. (For example, improvements in patient symptoms or problems from treatment or diagnosis.)

?The rate and severity of acute cellular rejection and antibody mediated rejection. ?The rate of delayed graft function, and duration of delayed graft function. ?The duration of hospitalization. ?The frequency of re-hospitalization. ?Graft survival. ?Patient survival. ?Development of new cancers in the post-transplant period.

Describe any health-related risks, side effects, or harms that you are concerned about.

?Infections (bacterial) infections ?Opportunistic infections including but not limited to reactivation of cytomegalovirus (CMV), Epestein-Barr virus (EBV), and polyoma virus (PV).

?Development of new malignancies such as post transplant lymphoproliferative disorders (PTLD), solid organ tumors, and skin cancers.

Appropriateness for EHC Program

Does your question include a health care drug, intervention, device, or technology available (or likely to be available) in the U.S.?

yes

Which priority area(s) and population(s) does this topic apply to? (check all that apply)

EHC Priority Conditions (updated in 2008)

Cardiovascular disease, including stroke and hypertension
Diabetes mellitus
Functional limitations and disability
Infectious diseases, including HIV/AIDS
Obesity

AHRQ Priority Populations

Low income groups
Minority groups
Women
Elderly
Individuals with special health care needs, including individuals with disabilities or who need chronic care or end-of-life health care

Federal Health Care Program

Medicaid
Medicare

Importance

Describe why this topic is important.

Recipients of deceased donor kidneys are at increased risk for acute rejection as well as delayed graft function and other complications associated with the development of both. These events in the immediate post-transplant period is associated with prolonged hospitalizations, delayed initiation of maintenance IS therapy, need for dialysis therapy in the post-transplant period, increase in the risk for cardiovascular events, and poor graft and patient survival. However, it is unclear at this time whether these three induction agents have different degrees of impact on these events in the peri-operative and post-transplant period. It is also not clear if these different agents have different magnitude of harm in the post-transplant period. It is not known whether these agents have different effects in different age groups and different ethnic groups of patients. Since during the year 2008, a total of 10,551 DDK transplants were performed, and 36% were aged 18-34, another 42% were aged 50-64 years, and 18% were age >65 years. Despite the evidence that thymoglobulin is more potent than basiliximab in reducing the rate of acute rejection, it is not known if alentuzumab is inferior to these agents in preventing these post-transplant events. Despite the evidence that thymoglobulin is superior in reducing the rate of acute cellular rejection compared to basiliximab, but it is not clear if alemtuzumab is equally potent. It is not conclusive if these three agents have similar efficacy and safety in different age groups and different races. Additionally, these agents have different costs and incremental cost analysis has not been studied. Moreover, long term safety of these induction agents with different degrees of immununodepletion properties are not known. It is not conclusive that treatment with these induction agents effectively and safely increases the one and five year graft and patient survival. Therefore, it is very imperative that safe and effective treatments tha

What specifically motivated you to ask this question? (For example, you are developing a clinical guideline, working with a policy with large uncertainty about the appropriate approach, costly intervention, new research you have read, items in the media you may have seen, a clinical practice dilemma you know of, etc.)

?Lack of consistency in using the induction therapy in recipients of deceased donor kidney recipients across the country due to different center specific protocols based on individual center preferences due to the paucity of robust evidence in favor or against each of these induction agents.

?There is a tremendous degree of uncertainty in deciding as to what induction agents among the three available agents confer the best risk/benefit ratio for these patients with CKD who have waited for years to receive the kidney transplant.

?So, studying the comparative effectiveness of these agents would allow us to solve this clinical practice dilemma and would offer the best evidence based treatment to our patients with CKD.

Does your question represent uncertainty for clinicians and/or policy-makers? (For example, variations in clinical care, controversy in what constitutes appropriate clinical care, or a policy decision.)

yes

If yes, please explain:

?Among the three frequently used induction agents, which one offers the best benefit to this high-risk patient population is not known? The immediate-term efficacy in terms of reduction in the rate of acute rejection, duration of DGF, patient survival, graft survival, and development of opportunistic infections are not available. Additionally, the risk of malignancies either hematological and/or solid organ malignancies in the post-transplant period remains unknown following induction therapy with each of these three agents.

Potential Impact

How will an answer to your research question be used or help inform decisions for you or your group?

?Among the three frequently used induction agents, only basiliximab is FDA approved for induction therapy in recipients of kidney transplants. On the other hand more and more centers are using other two (non-FDA) approved agents (Thymoglobulin and Alentuzumab) for induction therapy.

?At best, induction with alentuzumab reduces the rate of acute rejection during first year after transplant more effectively than the other two agents, and thymoglobulin is more potent than basiliximab in reducing the rate of acute rejection.

?Whether this benefit with the use of alentuzumab also translates into better graft and patient survival without additional risks for opportunistic infections, malignancies and other complications such as increased risk of antibody mediated rejection has not been established.

?Additionally, alentuzumab is easy to administer and its cost is much lower than the total cost of other two agents.

?A review on this topic may clarify the balance of potential benefits and risk of therapy of each of these agents. OR if the review does not answer the question, then a RCT is urgently warranted.

Describe the timeframe in which an answer to your question is needed.

?This is an urgent need as more and more transplant centers are using the non-FDA approved drug as an induction agent. Hence, an increasing number of patients with CKD after waiting for years for the kidney transplantation could be put at risk.

Describe any health disparities, inequities, or impact on vulnerable populations your question applies to.

?Wait-listed CKD patients have other complex medical problems as a consequence of CKD and also develop different types of medical complications while on dialysis therapy. Hence, a vulnerable population for future complications. ?Additionally, patients with CKD without or with the need for dialysis therapy often have disparities in outcome for non-dialysis or transplant related problems due to lack of evidence-based therapies compared to the general population.

?With a 30 percent increase in CKD over the past decade, the disease now affects

approximately 27 million people in the United States and accounts for more than 24 percent

of Medicare costs. CKD, like many other health conditions, disproportionately impacts ethnic

minorities. For the past three decades, the incidence of ESRD has increased at a rate four

times greater among African Americans compared to Caucasian.

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