THESIS PROTOCOL

DNB Nephrology

(Session March 2013-2016)

PROPOSED TOPIC OF THESIS

A study of induction with low dose rabbit anti

thymocyte globulin (rATG) in low risk living donor
renal transplant recipients and its correlation with
allograft survival

By: -

Dr. Jai Inder Singh

DNB Nephrology Trainee

Fortis Hospital, Noida

 THESIS PROTOCOL SUBMISSION FOR D.N.B. NEPHROLOGY

GUIDE

Dr. Manoj Kumar Singhal

Senior Consultant & Additional Director Department of Nephrology & Renal

Transplant Medicine

Fortis Hospital, Noida.

Signature

CO GUIDE

Dr. Anant Kumar

Senior Consultant, Department of Urology

Fortis Hospital, Noida.

Signature.

CO GUIDE

Dr. Alok Kumar Gupta

Senior Consultant, Department of Nephrology

Fortis Hospital, Noida.

 Signature.

CERTIFICATE FROM INSTITUTION

This is to certify that Dr. Jai Inder Singh enrolled as D.N.B. Nephrology session Feb,

2013, will be doing his thesis titled A study of induction with low dose rabbit anti

thymocyte globulin(rATG) in low risk living donor renal transplant recipients and its

correlation with allograft survival under guide Dr. Manoj Kumar Singhal , Senior

Consultant & Additional Director Department of Nephrology & Renal Transplant

Medicine, Co Guide Dr. Anant Kumar, Senior Consultant Department of Urology and

Dr. Alok Kumar Gupta, Senior Consultant Department of Nephrology. He will be

studying cases at Fortis Hospital, Noida.

Dr. Sudhir
Medical Superintendent & D.N.B. Coordinator

Fortis Hospital, Noida

 CERTIFICATE OF GUIDES

This is to certify that facilities of the work on the subject of thesis exist in

the hospital and will be provided to the candidate. We shall guide the candidate in this

work and see that the data being included in the thesis are genuine and the candidate

himself will do the work. It is also certified that no work has been done on this topic in

this institute earlier.

Guide

Dr. Manoj Kumar Singhal

Senior Consultant & Additional Director Department of Nephrology

Fortis Hospital, Noida.

CO GUIDE

Dr. Anant Kumar

Senior Consultant, Department of Urology

Fortis Hospital, Noida.

CO GUIDE

Dr. Alok Kumar Gupta

Senior Consultant, Department of Nephrology

Fortis Hospital, Noida.

CANDITATE

Dr. Jai Inder Singh

DNB Nephrology

NBE Registration No: awaited

Fortis Hospital, Noida.

 INTRODUCTION

The goal of organ transplantation is to provide durable organ function while minimizing

risks such as infection and cancer. Also on the background of a worsening disparity between

kidney transplant requirement and supply, prolonging the longevity of organs that undergo

transplantation is of primary importance. Rejection remains the achilles heel of graft survival.

Factors such as timing of rejection, severity and number of acute rejections, and degree of

recovery of function after treatment all affect the long-term outcome5. Acute rejection is most

frequent during the first few weeks after a transplant, but can occur at any time if the level of

immunosuppression becomes inadequate.

Induction therapy refers to the initiation of intense immunosuppression in the

initial days after transplantation when the recipient's immune system contacts donor antigens for

the first time to prevent early acute rejection episodes and is believed to prolong graft survival

while allowing for a lower overall intensity of maintenance immunosuppressant medications1..

Induction may also provide an immunosuppressive umbrella in situations like acute tubular
necrosis where one would want to reduce Calcineurin exposure for quicker recovery of renal

function without enhancing acute rejection rates. Induction therapy is accomplished by use of

potent and selective immunosuppressive agents at the time of transplantation The optimal agent

for induction therapy is not clear. Various centers and countries follow their own protocol for

induction therapy.

Rabbit antithymocyte globulin (rATG) [Thymoglobulin; Thymoglobuline] is a

purified, pasteurized preparation of polyclonal gamma immunoglobulin raised in rabbits against

human thymocytes that is indicated for the prevention and/or treatment of renal transplant

rejection. A large number of controlled randomized trials and meta-analyses indicate that

induction therapy consisting of rATG plus conventional immunosuppressive agent therapy is

superior to conventional agent therapy alone in reducing kidney allograft rejection and allograft

failure2,3. The KDIGO guidelines currently recommend use of rATG principally for groups at

high-risk for allograft rejection4. Full-dose rATG induction therapy (7-10 mg/kg) has been

associated with increased morbidity due to risks of overimmunosuppression.

Given the high cost of induction agents, the benefit of giving induction and the

dose in which they are administered is of great importance especially in countries like India

where patients directly pay for their immunosuppression. Induction may also provide an

immunosuppressive umbrella in situations like acute tubular necrosis where one would want to

reduce CNI exposure for quicker recovery of renal function without enhancing acute rejection

rates. Induction therapies such as rATG contribute to improved allograft survival in high risk

recipients but the effectiveness of low dose rATG is not well defined in low risk patients despite
widespread use in this subgroup of patients. There is paucity of data regarding the benefit of low

dose rATG in low risk patients for induction therapy in renal allograft recipients. This study aims

to look at the aspect of effectiveness of low dose induction with rATG in low risk renal transplant

recipients.

AIMS AND OBJECTIVES

1. To establish the correlation between low dose rATG used for induction and incidence of

acute rejection and allograft loss at one year post transplant in low risk living donor

kidney transplant recipients.

2. To study the prevalence of delayed graft function in patients receiving low dose rATG.
3. To study the safety and incidence of infections in patients receiving low dose rATG.
4. To compare between the two strategies of no induction versus induction with rATG in

low risk living donor kidney transplant recipients and:

a. Allograft survival at one year post transplant.
b. Patient survival at one year post transplant.
c. Serum creatinine at six months and one year post transplant.
 REVIEW OF LITERATURE

INDUCTION IN RENAL TRANSPLANT

Induction therapy in renal transplantation provides improved short- and long-term

graft outcomes compared with placebo. Current immunosuppressive therapies and protocols

have led to significant improvements in early patient and graft survival rates following kidney

transplantation. Induction immunosuppressive strategies utilized by kidney transplant centers fall

into one of the two categories. High doses of conventional immunosuppressive agents, while the

other utilizes antibodies directed against T-cell antigens in combination with lower doses of

conventional agents (TABLE 1) .

Induction in renal transplant

High dose conventional agents Antibody induction

Calcineurin inhibitor: Cyclosporine or Reduced dose or delayed introduction of calcineurin

tacrolimus inhibitor: Cyclosporine or tacrolimus (lower doses
than conventional agent strategy)

Corticosteroid Corticosteroid

Antimetabolite: Mycophenolate Antimetabolite: Mycophenolate mofetil (MMF),

mofetil (MMF), mycophenolic acid mycophenolic acid (MPA), or azathioprine
(MPA), or azathioprine

Plus one of the following:

 rATG

Basiliximab

Alemtuzumab

These agents provide a high degree of initial immunosuppression when the risk of rejection is

the highest. These agents are all clinically effective in transplantation. Two depleting agents

( rATG and Alemtuzumab) and one non depleting agent (basiliximab) are currently available and

widely in use. Depleting agents are associated with more complications, such as infection and

malignancy. Induction therapy by targeting T lymphocytes has become the standard of care in the

majority of transplant centers. KDIGO transplant guidelines currently recommend use of an IL2-

RA [interleukin- 2 receptor antagonist] as the first line induction therapy and T-cell depleting

agents for high risk recipients. Anti-lymphocyte antibodies include both polyclonal and

monoclonal antibodies. Thymoglobulin (Genzyme, Cambridge, MA) is a polyclonal

immunosuppressive agent that is generated in rabbits. Although there is no generic formulation,

it is commonly referred to as rATG.

Rabbit antithymocyte globulin (rATG)

Rabbit antithymocyte globulin (rATG) is a polyclonal antilymphocyte globulin which depletes

lymphocytes in the blood and peripheral lymphoid tissue. rATG is a polyclonal gamma

immunoglobulin raised in rabbits against human thymocytes that is indicated for the prevention

and/or treatment of renal transplant rejection. It was approved for the treatment of rejection by

the US Food and Drug Administration in 1999. Thymoglobulin is now the most widely used
polyclonal induction agent in the United States, although notably, its use as an induction agent

technically is an off-label indication. The use of rATG has been steadily increasing in the US as

is evident from the graph taken from Scientific Registry for Transplant Recipients 2007 Annual

Report (www.unos.org). The latest data from US indicates that induction with T-cell depleting

agents stands at 55.7% in kidney transplant recepients. (Scientific Registry of Transplant

Recipients, Accessed 2013. Available at http://www.ustransplant.org). The use of induction

agents is increasing in India but there does not exist any centralized data on the percentage of

patients receiving induction.

Trends in the use of induction antibodies in the United States from 1997 to 2006. From the Scientific

Registry for Transplant Recipients 2007 Annual Report (www.unos.org)

Mode of action:
 rATG exerts its immunomodulatory and immunosuppressive effects via a wide range of

immune and non-immune targets, adhesion molecules, and chemokine receptors [Popow I,

Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger GJ, Kundi M, et al. A

comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte

globulin preparations. Am J Transplant. 2013;13:310313.]. rATG administration induces a

significant depletion of CD3+, CD4+ and CD8+ T-cells and NK cells, as well as other T-cell

subsets [11 Popow I ], while leaving the B-cell count unaffected [Buchler M, Longuet H,

Lemoine R, Herr F, Gatault P, Thibault G, et al. Pharmacokinetic and pharmacodynamic studies

of two different rabbit antithymocyte globulin dosing regimens: results of a randomized trial.

Transpl Immunol. 2013;28:1206.]. CD3+ cell count diminishes rapidly, with most patients

having almost no CD3+ cells within 24 h after the start of treatment [Ternant D, Buchler M,

Thibault G, Ohresser M, Watier H, Lebranchu Y, et al. Influence of FccRIIIA genetic

polymorphism on T-lymphocyte depletion induced by rabbit antithymocyte globulins in kidney

transplant patients. Pharmacogenet Genomics. 2014;24:2634.]. The proportion of nave CD4+

cells decreases, while central memory CD4+ T-cells increase. Using a typical dosing strategy of

1.5 mg/kg on days 03 (cumulative dose 6 mg/kg), rATG remains at therapeutic levels for

approximately 19 days [Buchler M, Longuet H, Lemoine R, Herr F, Gatault P, Thibault G, et al.

Pharmacokinetic and pharmacodynamic studies of two different rabbit antithymocyte globulin

dosing regimens: results of a randomized trial. Transpl Immunol. 2013;28:1206. ]. The half-life

of rATG is about 3 weeks, with complete elimination from the serum within 1 year

[Ternant D, Buchler M, Thibault G, Ohresser M, Watier H, Lebranchu Y, et al. Influence of

FccRIIIA genetic polymorphism on T-lymphocyte depletion induced by rabbit antithymocyte

globulins in kidney transplant patients. Pharmacogenet Genomics. 2014;24:2634.].

 rATG depletes lymphocytes in the blood and peripheral lymphoid tissue. T-cell depletion is

accomplished by inducing complement-dependent cell lysis, apoptosis, and modulation of cell

surface and adhesion molecules that regulate T-cell function and leukocyte endothelial

interactions, respectively.Polyclonal depleting agents contain antibodies to a wide variety of

human T-cell surface antigens, including the major histocompatibility complex antigens. They

also may contain antibodies against a variety of other antigens, including those present as surface

molecules on granulocytes and platelets, and cellular adhesion molecules on endothelium.

Although the full array of mechanisms by which these agents suppress immune response is not

completely understood, T-cell depletion is an important factor. Antibody-mediated T-cell

opsonization and complement-dependent cytotoxicity yield altered T cells that subsequently are

cleared by the reticuloendothelial system (spleen, liver, and lungs The exact mechanisms

accounting for the effectiveness of rabbit antithymocyte globulin are not entirely understood.

Modulation of T-cell activation and chemotaxis also may be involved. T-cell depletion is

accomplished by inducing complement-dependent cell lysis, apoptosis, and modulation of cell

surface and adhesion molecules that regulate T-cell function and leukocyte endothelial

interactions, respectively. (1, 2, 6) (Impact of Small Variations in the Delivered Dose of Rabbit

Antithymocyte Induction Therapy in Kidney Transplantation With Early Corticosteroid

Withdrawal, Demetra S. Tsapepas,)

Indication of rATG in KTR:

High risk recepients have been shown to benefit from induction therapy. In a single-center

RCT, sensitized patients were randomized to induction with ATG or no induction. Patients

treated with ATG had a reduction in acute rejection and improvement in graft survival
( Thibaudin D, Alamartine E, de Filippis JP et al. Advantage of antithymocyte globulin

induction in sensitized kidney recipients: A randomized prospective study comparing induction

with and

without antithymocyte globulin. Nephrol Dial Transplant 1998; 13: 711715)

Definitions of high risk vary between studies, as do induction and maintenance

dosing regimens. Patients are considered high risk if they had a history of prior renal allograft

transplantation, multiple blood transfusions, more than 50% HLA mismatch, peak percent PRA

was greater than 50, presence of donor specific antibody(DSA) or Delayed graft function(DGF).

Risk factors for acute rejection include

The number of human leukocyte antigen (HLA) mismatches (A)

Younger recipient age (B)

Older donor age (B)

PRA >0% (B)

Presence of a donor-specific antibody (B)

Blood group incompatibility (B)

Delayed onset of graft function (B)

Cold ischemia time >24 hours (C)

where A is the universal agreement, B is the majority agreement and C is the single study.
 Younger recipients may also be better able to tolerate serious adverse effects of

additional immunosuppressive medication, making it compelling to treat younger recipients with

lymphocytedepleting antibody than IL2-RA (KDIGO). Induction with a lymphocyte depleting

agent could be used when there is an increased risk for DGF, such as in cases with expanded

criteria donation or prolonged cold ischemia time. Depleting antibodies are superior to prevent

acute rejection, but there is uncertainty whether this corresponds to improved graft outcomes.

Depleting antibodies are associated with more infections. Use of rATG in low risk patients is also

increasing although there are no good studies as yet regarding its dosage and benefits in these

group of patients. Their are centre specific preferences for its use in low risk patients in the

absence of any large randomized trials and guidelines.

DOSE OF rATG FOR INDUCTION

The dose of rATG and duration of therapy required to achieve protection from rejection

and graft failure remain uncertain. The potential deleterious effects of rATG in relation to the

risks of infection and malignancy, in addition to the significant associated costs, demand the

exploration of the efficacy of this drug at lower exposures. A variety of successful therapeutic

strategies have been employed including both short and long courses consisting of total doses

ranging from 3 to 10.5 mg/kg. To a great extent, the dose requirement for rATG may depend on

the character of the patients to be treated, but the optimal dose is not well established. The dose

of ATG may be decided as per the immunological risk of the patient

The dose of ATG has been examined in various studies with different protocols.

These studies have looked at different clinical as well as laboratory markers of

immunosuppression after different dosages of rATG. Clinical marker was event of acute rejection
whereas lab markers were T cell counts and hematological markers. The appropriate rATG dose

for induction therapy in low-risk renal recipients is not well defined or approved however it is

being increasingly used in low risk patients with the goal of reducing early allograft rejection and

thereby improving long term graft survival. The safe and effective dosing of rATG in low

immunologic risk recipients would require a randomized, prospective trial. The currently

available data are of generally low quality, based on many small and often retrospective studies.

Despite extensive clinical use of rATG for induction immunosuppression in adult kidney

transplant recipients, the ideal dose and duration of therapy are still empirical in many centers

where various protocols exist, and over-immunosuppression remains a concern.

In the initial studies establishing the efficacy and safety of rATG, patients received

total cumulative doses in the range of 8- to 11-mg/kg rATG. These doses were administered for

a period of 7 to 10 days and were followed by triple-drug maintenance immunosuppressive

regimens that were considered standard therapy at the time. Full-dose rATG induction therapy

(710 mg/kg) has been associated with increased morbidity. The optimal dose often is quoted

as a total of 6 mg/kg, and a typical regimen of Thymoglobulin for induction consists of 1.5

mg/kg for 3 to 5 days. However, dosing protocols have a wide range from 1 to 6 mg/kg/dose for

a duration of 1 to 10 days.47,50-55

47. Brennan DC, Flavin K, Lowell JA, et al: A randomized,

double-blinded comparison of Thymoglobulin versus
Atgam for induction immunosuppressive therapy in adult
renal transplant recipients. Transplantation 67:1011-1018,
1999

50 Goggins WC, Pascual MA, Powelson JA, et al: A

prospective, randomized, clinical trial of intraoperative versus
postoperative Thymoglobulin in adult cadaveric renal
transplant recipients. Transplantation 76:798-802, 2003
51. Agha IA, Rueda J, Alvarez A, et al: Short course
induction immunosuppression with thymoglobulin for renal
transplant recipients. Transplantation 73:473-475, 2002
52. Peddi VR, Bryant M, Roy-Chaudhury P, et al: Safety,
efficacy, and cost analysis of thymoglobulin induction therapy
with intermittent dosing based on CD3_ lymphocyte counts
in kidney and kidney-pancreas transplant recipients. Transplantation
73:1514-1518, 2002
53. WongW, Agrawal N, Pascual M, et al: Comparison of
two dosages of thymoglobulin used as a short-course for
induction in kidney transplantation. Transpl Int 19:629-635,
2006
54. Gurk-Turner C, Airee R, Philosophe B, et al: Thymoglobulin
dose optimization for induction therapy in high risk
kidney transplant recipients. Transplantation 85:1425-1430,
2008
55. Stevens RB, Mercer DF, Grant WJ, et al: Randomized
trial of single-dose versus divided-dose rabbit anti-thymocyte
globulin induction in renal transplantation: An interim
report. Transplantation 85:1391-1399, 2008

rATG dosing has decreased over time, refining the risk:benefit ratio and reducing early

safety concerns. Higher doses and prolonged periods of induction increase the risk of infection

and the potential development of lymphoma, whereas low doses less than 3 mg/kg may not

effectively prevent acute rejection.

The dose of rATG recommended for prevention of renal allograft rejection ranges from 1 to10

mg/kg given over 1 to 10 days6, 7, 8. In animal models, higher initial doses of shorter duration

approximating a human-equivalent dose of 6 mg/kg were associated with more peripheral and

central lymphocyte depletion and better allograft survival9 . Higher doses and prolonged duration

of induction agents are thought to be associated with an increased risk of infection and the

potential development of lymphoma, while low doses of less than 3 mg/kg may not effectively

prevent acute rejection10. A dose of rATG less than or equal to 3 mg/kg has been considered as

low dose for induction by Laftavi et al in their study. (Low-Dose Thymoglobulin Use in Elderly

Renal Transplant Recipients Is Safe and Effective Induction Therapy M.R. Laftavi, S. Patel,

DOI: http://dx.doi.org/10.1016/j.transproceed.2011)

Wong W et al. evaluated the degree and durability of T-cell clearances

with two different thymoglobulin regimens in adult kidney transplant recipients (KTR)11. Seven
KTR received a 3-day thymoglobulin-based induction of 1.0 mg/kg/day while nine received 1.5

mg/kg/day, in addition to maintenance immunosuppression. Renal function, infections and

malignancies were monitored for 24 months. Renal function between the two groups was not

significantly different at 6- and 24-months post-transplant implying the efficacy of low dose

thymoglobulin (3 mg/kg). No acute rejection episodes, cytomegalovirus infections, or

malignancies were noted in either group. Thymoglobulin induction was efficacious in both

groups, but with a significantly sustained T-cell clearance in the 1.5 mg/kg/day regimen. A more

profound T-cell clearance within the first 6 months post induction therapy may translate into a

decreased risk of immunological injury and improved long-term outcome after kidney

transplantation but maybe at the cost of increased risk of infections.

A study by Gurk-Turner C compared two doses of ATG (less than or equal to 7.5mg/kg

and more than 7.5 mg/kg) in high risk kidney transplant recipients6. Total rATG doses less than

or equal to 7.5 mg/kg were safe and effective in achieving a low rate of allograft rejection and

graft outcomes comparable to higher doses. The Thymoglobulin Antibody Immunosuppression

in Living Donor Recipients (TAILOR) registry12 was established to assess clinical experience

with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant

recipients. The mean cumulative dose of rATG induction was 5.29 mg/kg with a trend to dose

reduction towards the end of the study. The decline in dose may be a result of an intentional dose

titration over time to find the minimum effective dose that still allows for minimization of

maintenance immunosuppression. Among patients enrolled in the TAILOR registry, 6- and 12-

month biopsy proven acute rejection (BPAR) rates were 6.5% and 8.3%, respectively, with the

majority reported as mild in severity. Long term data from over 2000 LD transplant recipients
showed that rATG was generally safe and was associated with similar post transplantation

complications and patient and graft survival to that of the national LD transplant population13.

M.R. Laftavi et al14 compared low dose rATG with basiliximab for induction

therapy in low-risk renal transplant recipients and found that rATG was associated with a lower

rate of acute rejection (7.8% vs. 35%, P _ .01) and better mean serum creatinine at 3 and 5 years

(1.2 vs. 1.5, P _ .02 and 1.18 vs. 1.54, P _ .04, respectively) although long term graft survival

was the same in living donor recepients. For deceased donor recepients, low dose rATG was

associated with a better long-term graft survival (86% vs. 76%, P _ .02). A retrospective study

from another center found that rATG compared with no induction was associated with a

significantly decreased acute rejection rate (2 vs. 48 %) without an increase in post transplant

complications15.

Demetra S. Tsapepas studied effect of minor variations (< 1 mg/kg) in rATG dose

with early steroid withdrawal on graft survival and found that even small reduction in the total

delivered dose of rATG, resulting from rounding to the nearest vial size had an adverse impact

on early (< 90 days after transplantation ) rejection-free graft survival16. Overall biopsy proven

acute rejection (BPAR) rates at the time of last follow-up demonstrated statistically significant

outcomes. Hammond EB et al conducted a study which showed that patients who did not receive

induction therapy were almost twice as likely to have an acute rejection compared to those that

did receive induction17

Klem P et al ( Reduced Dose Rabbit Anti-Thymocyte Globulin Induction for Prevention

of Acute Rejection in High-Risk Kidney Transplant Recipients
Klem, Patrick; Cooper, James E.; Weiss, Andrew S.; More
Transplantation. 88(7):891-896, October 15, 2009.)
retrospectively analyzed outcomes of 83 kidney transplant recipients at increased risk for acute

rejection (repeat transplant, African American race, and panel reactive antibody > or =20%) from

July 2004 to July 2007 who were treated with rATG 1.5 mg/kg per day for 3 (n=39) or 4 (n=44)

doses for induction to determine the impact of reduced-exposure ATG in the prevention of acute

rejection. ATG was initiated intraoperatively and continued on consecutive days. All patients

received triple maintenance immunosuppression including prednisone and calcineurin inhibitor.

Patients requiring dialysis within 48 hr after transplant were excluded from analysis. One-year

acute rejection rates were 10% and 11% in the 3- and 4-dose cohorts, respectively, with 100%

patient and graft survival at 1 year in both groups. Patients in the 3-dose cohort were discharged

from the hospital sooner than the 4-dose cohort (median length of hospital stay, 3 vs. 4 days;

P=0.004). The results suggest that a 3- or 4-dose course of rATG (1.5 mg/kg/dose) provides

excellent protection against acute rejection even in patients at increased risk, with the potential

for cost savings from a reduction in hospital stay and medication administration

Hence most of the study results favour administering rATG for induction

immunosuppression but the doses used are variable and require further investigation to know the

optimal dose effective in prolonging allograft and patient survival. Majority of the studies till

date have concluded that lower dose of rATG use does not negatively impact the graft and

patient survival compared to the higher doses initially recommended.

Effect of dosage pattern

There are few studies evaluating how rATG should be administered for induction

In one study, a single infusion of 6 mg/kg instead of four divided doses of 1.5 mg/kg/day was
found to offer improved renal function at month 6 after kidney transplantation [Stevens RB,
Mercer DF, Grant WJ, Freifeld AG, Lane JT, Groggel GC, et al. Randomized trial of single-dose
versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim
report. Transplantation. 2008;82:13919.]
 rATG infusion before renal allograft reperfusion improves early graft function but
infusing a large rATG dose over a short interval was evaluated by Stevens RB et al (A
Randomized 22 Factorial Trial, Part 1: Single-Dose Rabbit Antithymocyte Globulin Induction
May Improve Renal Transplantation Outcomes R. Brian Stevens,1 Kirk W. Foster,2 Clifford D.
Miles,3 James T. Lane,4 Andre C. Kalil,3 Diana F. Florescu,3 John P. Sandoz,5 Theodore H.
Rigley,1 Kathleen J. Nielsen,2 Jill Y. Skorupa,1 Anna M. Kellogg,3 Tamer Malik,1 and Lucile E.
Wrenshall1. Transplantation 2015;99: 197209 ) for its effect on renal function and allograft
nephropathy in a prospective, randomized comparison against conventional rATG induction. A
prospective, randomized, nonblinded trial to evaluate the two rATG dosing protocols (single
dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed
after 6 months by calcineurin-inhibitor withdrawal was done. Primary endpoints were renal
function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at
protocol biopsy. Secondary endpoints included patient survival, graft survival, biopsy-proven
rejection, and infectious or noninfectious complications. There were significantly fewer deaths
among kidney recipients who received SD rATG induction. No statistically significant
differences were present between induction groups in death-censored or rejection-free graft
survival. There were significantly fewer deaths among kidney recipients who
received single dose rATG induction. The long-term data now seem to show that SD
rATG associates with superior patient survival, improved early (all donor types), and long-term
deceased-donor graft function, fewer infections, and fewer multiple infections. This study
demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with
improved early renal function compared with administering rATG in alternate-day doses. Hence
how rATG is administered may impact its efficacy and safety.

The rATG is usually administered as a series of small doses spaced at 1-day or 2-day

intervals. However, more intensive administration (fewer, larger doses) may confer more

comprehensive lymphocyte depletion, both peripherally and in secondary lymphoid structures.(

Preville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin

immunosuppressive activity in a nonhuman primate model. Transplantation 2001;71:460)

Effect of dosage on T-cell population

The degree and durability of T-cell clearances was evaluated

with two different thymoglobulin regimens in adult kidney transplant recipients (KTR) by Wong

W et al. Seven KTR patients received a 3-day thymoglobulin-based induction of 1.0 mg/kg/day

while nine received 1.5 mg/kg/day, in addition to maintenance immune suppression. Lymphocyte
subsets were monitored for 6 months. Renal function, infections and malignancies were

monitored for 24 months. T-cell subsets were significantly lower by day 30 with

the thymoglobulin 1.5 mg/kg/day regimen when compared with the 1.0 mg/kg/day regimen; this

trend was sustained at 6-month (CD3+: 438 +/- 254 vs. 1001 +/- 532 cells/mm 3, P = 0.016).

Renal function between the two groups was not significantly different at 6- and 24-months post-

transplant. One case of BK Virus viremia in the 1.5 mg/kg/day thymoglobulin group was

detected. No acute rejection episodes, cytomegalovirus infections, or malignancies were noted in

either group. Thymoglobulin induction was efficacious in both groups, but with a significantly

sustained T-cell clearance in the 1.5 mg/kg/day regimen. A more profound T-cell clearance

within the first 6 months post induction therapy may translate into a decreased risk of

immunological injury and improved long-term outcome after kidney transplantation34

Standard doses (7-10 mg/kg) of ATG result in profound lymphopenia and predispose patients

to infection and malignancy. The effects of lower doses of ATG (LoD-ATG, 3-5 mg/kg) on

peripheral blood lymphocytes (PBL) was studied in a prospective clinical trial by Pankewycz O

et al, PBL subsets were characterized by flow cytometry over 12 months following LoD-ATG

therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid,

and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or

sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-

ATG therapy resulted in prolonged suppression of CD19+ B cells, total CD3+ T cells, as well as

nave and memory CD4+ T cell and CD4/CD25/Foxp3+ T-regulatory subsets irrespective of

chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA+

nave T-cell subset resulting in an altered memory/nave CD4+ ratio. LoD-ATG failed to deplete
CD8+ T cells, which increased their relative contribution to the total CD3+ pool. All other

lymphocyte subsets maintained near normal proportions. Thus, LoD-ATG therapy may lessen the

adverse effects of full dose ATG while maintaining overall efficacy.

Kho MM et al studied the effect of low and ultra-low dosages Thymoglobulin (Genzyme) on

peripheral T, B, and NK cells. Kidney transplant recipients received either 0.5 mg/kg, 1.0 mg/kg

or 2.0 mg/kg on the first 3 consecutive days post-transplantation. Thus, total doses were 1.5

mg/kg, 3.0 mg/kg and 6.0 mg/kg. A total of 40 patients were enrolled, including 11 controls. All

patients were treated with Prednisolon, Advagraf (Astellas) and Mycophenolate Mofetil (Roche).

T (CD3+), B (CD19+) and NK (CD3-CD16+56+) cells were analyzed by flow cytometry.

Baseline cell counts were compared to forty age and sex matched healthy persons. Post-

transplantation cell counts of the 3 Thymoglobulin groups were compared to the 11 control

patients, who received no induction therapy. Absolute numbers of T, B, and NK cells were

comparable in all patients pre-transplantation, but T and B cells were lower than in healthy

persons (p=0.007 and p=0.0003, Mann Whitney test). In the first week, T cells and NK cells

were significantly lower in all Thymoglobulin groups compared to controls. B cells were not

affected. One month after Thymoglobulin NK cells had returned to control numbers in all

groups, while T cells had already recovered to control counts in the 1.5 mg/kg group. During

follow-up, T cells in the 3.0mg/kg group also returned to control values, but at one year the

patients in the 6.0 mg/kg group still had significantly lower T cells (p=0.03). Patient and graft

survival, rejection and infection incidence and renal function did not differ between group.

Patients with end stage renal disease have significantly lower peripheral T and B cell counts than

healthy persons. (Ultra-) low Thymoglobulin schedules deplete peripheral lymphocytes in a dose
dependent way. Knowledge of the duration of this depletion contributes to finding the optimal

immunosuppressive strategy for kidney transplant recipients

Grafals M et al compared 2 low dose regimen of 2.25 mg/kg and 3.75 mg/kg. Acute rejection rate was
almost same (10% vs 9.5%) but DGF was more frequent in 2.25 mg/kg group (40% vs. 14.3 %; p =
0.041)
(Grafals M, Simpson M, Gilligan H, Pomposelli J, Akoad M, Kwaja K, et al. Prospective randomized
study of low dose antithymocyte globulin as induction in non sensitized adult renal transplant recipients
[abstract no. 1351]. Am J Transplant. 2013;13 Suppl 5.)

Cost- Benefit analysis

Given the high cost of rATG it is important to know the minimum required dose which will

allow optimal graft and patient survival. especially in a developing country like India where cost

decide whether or not a patient gets a transplant. The immunosuppressive effects of and costs

associated with short-course antithymocyte globulin rabbit (ATG [rabbit]) therapy versus

standard-course ATG (rabbit) therapy in deceased-donor renal transplant recipients were

evaluated by Marfo K et al.

There is also evidence that a shorter coursefor example, 3 days at 2 mg/kg/day versus 4 days at
1.5 mg/kg/daymay result in indirect cost savings, largely due to reduced hospital stay
[Hardinger KL, Rasu RS, Skelton R, Miller BW, Brennan DC. Thymoglobulin induction dosing
strategies in a low-risk kidney transplant population: three or four days? J Transplant.
2010;2010:957549.
Marfo K, Akalin E, Wang C, Lu A. Clinical and economic analysis of short-course versus
standard-course antithymocyte globulin (rabbit) induction therapy in deceased-donor renal
transplant recipients. Am J Health Syst Pharm. 2011;68:227682.].
Dosing based on CD3? monitoring may also lower drug costs versus a fixed-dose regimen [Uber
WE, Uber LA, VanBakel AB, Crumbley AJ 3rd, Pereira NL, Ikonomidis JS, et al. CD3
monitoring and thymoglobulin therapy in cardiac transplantation: clinical outcomes and
pharmacoeconomic implications. Transplant Proc. 2004;36:32459.].
The records of 84 consecutive patients who received a deceased-donor renal transplant at the

Montefiore Einstein Center for Transplantation in 2008 were retrospectively reviewed. Donor

and recipient characteristics, including rates of biopsy-confirmed acute rejection, serum

creatinine (SCr) levels, and frequency of complications, and drug costs were collected. Patients
were excluded if they had donor-specific antibodies identified before transplantation or hepatitis-

C-positive serology or were under 18 years of age. A total of 60 patients were included in the

study, with 28 receiving short-course ATG (rabbit) therapy and 32 receiving standard-course

ATG (rabbit) therapy. Baseline patient demographic characteristics were similar between groups.

Six months after transplantation, biopsy-confirmed acute rejection episodes did not significantly

differ between the short-course ATG (rabbit) and standard-course ATG (rabbit) groups (17.8%

versus 12.5%, respectively), nor did SCr concentrations (1.56 mg/dL versus 1.85 mg/dL). The

frequency of therapy-related leukopenia was greater in patients receiving standard-course ATG

(rabbit). Patients treated with short-course ATG (rabbit) received a total mean dose of 4.6 mg/kg,

compared with 7.3 mg/kg for patients in the standard-course ATG (rabbit) group, resulting in a

mean cost saving of $2548 per patient. After six months, there were no significant differences in

biopsy- confirmed acute rejection episodes or SCr levels between deceased-donor renal

transplant recipients receiving short-course versus standard-course ATG (rabbit) induction

therapy. The mean cost saving associated with short-course therapy was $2548 per patient.

rATG vs Basiliximab

The benefit and risks associated with low-dose (Lo) rabbit antithymocyte globulin (rATG; 3-5

mg/kg total) induction in a low-risk population were looked into by Laftavi et al. They reported

the long-term outcomes in this patient population. They defined low risk as white, panel-reactive

antibody <30%, and non-Donor with Cardiac Death (DCD) recipients. They compared the risk of

acute rejection and graft survival for both living donor (LD) and deceased donor (DD) recipients.

The average dose of rATG was 3.11.2 mg/kg. Forty DD recipients received basiliximab (BSX)
and 145 patients were induced with Lo ATG. Twenty LD recipients received BSX and 64

received Lo ATG. The groups did not differ in demographics, donor characteristics, and

maintenance immunosuppression. At 8 years, patient survival was higher for LD patients

compared to DD recipients (91% vs 45%, P=.004). In recipients of LD kidneys, 8-year patient

survivals were not different comparing Lo rATG and BSX groups (92% vs 91%, respectively,

P=.55). In LD, 8-year graft survival was excellent irrespective of induction (Lo rATG 100% vs

BSX 98%); however, Lo rATG was associated with a lower rate of acute rejection (7.8% vs 35%

BSX, P<.01) and better mean serum creatinine at 3 and 5 years (1.2 vs 1.5, P=.02 and 1.18 vs

1.54, P=.04, respectively). For DD, Lo rATG was associated with a better long-term graft

survival (86% vs 76% BSX, P=.02). Viral infections and cancer rates were similar for Lo rATG

and BSX. Thus, we conclude that Lo rATG induction may add long-term benefit in low-risk

patients compared to anti-interleukin-2 receptor therapy without incurring additional risks of

infectious or malignant diseases.

Infections

Concerns about infectious complications associated with rATG therapy focus on viral infections,
most notably CMV infection. Randomized trials of rATG induction versus no induction [16, 17],
published in the early 2000s, reported a higher rate of CMV infection in kidney transplant
patients receiving rATG [16, 17]. In these studies, the dose of rATG was relatively high by
todays standards (12.5 mg/kg), and CMV prophylaxis was not specified. Higher rATG doses
appear to increase CMV infection rates compared with IL-2RA induction [47, 91]. In a United
Network for Organ Sharing (UNOS) analysis of 2,322 patients undergoing kidney
transplantation with rATG induction during 20032008, a period when rATG dose was declining,
the CMV infection rate was reported to be only 4.2 % [68]. It would appear that with
contemporary rATG dosing regimens, and wider use of CMV prophylaxis therapy, the risk of
increased CMV infections in rATG-treated kidney transplant patients has diminished but cannot
be discounted.
A more recent potential safety issue to emerge is whether rATG therapy could impact
on the risk of BK virus infection after kidney transplantation. A recent retrospective,
single-center analysis, which did not specify rATG dose, found no relationship between rATG
administration and risk of BK virus infection on multivariate analysis [215]. Generally, BK virus
infection is considered to be associated with any intensive immunosuppressive regimen rather
than a specific agent [216], and no direct link to rATG therapy has been established
[217].

Side effects

Depleting agents are associated with more complications, such as infection and malignancy.

The risk-benefit analysis in a study by Wagner SJ et al indicates that basiliximab may be the

preferred agent in low risk population. Use of induction therapy, particularly with rATG, may not

only allow for but also mandate reduction of maintenance immunosuppression.27

Both induction and treatment with rATG are generally well tolerated, although adverse

events, such as fever, leukopenia and thrombocytopenia, appear more common with rATG than

with other antibody preparations. Anaphylaxis, although rare, has been reported. .

Thymoglobulin is contraindicated in patients with an acute viral illness or history of allergy to

rabbit proteins.

The overall incidence of infection associated with rATG induction is generally no different from

that seen with eATG or basiliximab induction.

The incidence of malignancies is generally low with rATG therapy and generally does not

differ from that seen with other agents. Further prospective comparative studies would be

beneficial in order to definitively position rATG with respect to other antibody preparations. In

the meantime, available clinical data suggest that rATG is an effective and generally well

tolerated option for the prevention and treatment of acute renal graft rejection in renal transplant

recipients28.
Effect of rejection:

Acute rejection episodes are generally associated with a reduction in long-term allograft

survival..

MATERIALS AND METHODS

This was a single center, open label, prospective observational

study with follow-up data analysis at 6 months and 1 year. Approval was obtained

from the Institute Ethics Committee and informed consent was obtained from all

the patients. A bidirectional observational study was conducted among 100 renal

transplant recipients at a tertiary care centre in Noida. Patients undergoing

transplant from June 2012 to May 2014 will be studied and followed up till Apr

2015. All patients were offered rATG induction therapy. Those patients who opted
for the induction regimen constituted the rATG group while the rest constituted the

control group. All patients received tacrolimus at 0.15 mg/kg/day, mycophenolate

1 g twice daily and 20 mg of prednisolone daily (tapered to 5 mg over the next 8

weeks). Our protocol is risk adjusted such that patients who are at a higher risk for DGF or AR

received RATG and all other patients receive anti-CD25 Ab All consecutive low risk living

donor renal transplant recipients will be evaluated and those who receive low dose

rATG as a part of induction regimen will be included in the study group. Low dose

will be defined as 3mg /kg of rATG or less. The patients who do not receive rATG

induction will be taken as the control group. Patients are considered high risk if

they had a history of prior renal allograft transplantation, multiple blood

transfusions, more than 50% HLA mismatch, presence of donor specific antibody

or if their peak percent PRA was greater than 50. All patients who are to have

renal transplant are offered rATG induction in our institution based on their

immunological risk, risk of infection and socioeconomic status. Patients with

delayed or slow graft function get additional dose of rATG.

TYPE OF STUDY Bidirectional Observational Study

STUDY GROUPS

Group 1 (Control Group) Patients who receive no induction therapy

Group 2 (Treatment Group) Patients who receive low dose rATG ( 3 mg/kg) as induction

therapy.
INCLUSION CRITERIA

1. Age 18 years or more.

2. Patients who are recipients of living donor kidney transplant.
3. Patients who consent to participate in the study

EXCLUSION CRITERIA

1. Patients who refuse to participate in the study.

2. Patients who could not be administered rATG due to allergic reaction.
3. Patients receiving induction with agents other than rATG.
4. Previous exposure to lymphocyte depleting therapies.
5. Recipients of a simultaneously transplanted nonrenal solid organ.

Induction protocol

Patients will receive Thymoglobulin (rATG) as part of their induction

immunosuppressive protocol. The first dose will be given, a day prior to transplant of the

allograft. A maximum of 150 mg will be given in a day and remaining amount will be

administered on subsequent days till the cumulative dose of 3 mg/kg is reached.

Dose Modification: Thymoglobulin dose will be reduced if the white blood cell (WBC) or the

platelet count dropped below predefined critical values:

WBC Platelets rATG Dose

2000 to 3000 cells/mm3 75,000 cells/mm3 Reduce dose by half
2000 cells/mm3 50,000 cells/mm3 No rATG administered
Maintenance therapy

All patients will be initiated on intravenous methylprednisolone (500 mg) intraoperatively. Oral

prednisone 20 mg/ day is started on POD 1, and then tapered by 5mg every two weeks to a daily

maintenance dose of 5 mg/ day. MMF 1000 mg twice daily is initiated a day prior to the day of

surgery, reduced to 500 mg thrice a day at the time of discharge and subsequently maintained at

500 mg twice daily. The patients will be started on twice daily 0.1 mg/kg of tacrolimus. Target

trough levels of 6-8 ng/ml till six months post transplant and 4-6 ng/ml thereafter will be aimed

at in the treatment group. The level in control group will be 8 12 ng/ml in first two months, 6-8

ng/ml from second to sixth months and 4-6 ng/ml thereafter.

Infection Prophylaxis:

All patients in study group received trimethoprim/sulfamethoxazole for Pneumocystis carinii

pneumonia prophylaxis starting at POD 2 for 3 months. Patients in the low dose ATG

group were not given CMV prophylaxis considering them to be at low risk of

CMV disease. High dose ATG group received 3 months of Valgancyclovir

prophylaxis. CMV testing was done with CMV DNA PCR for all the patients at

intervals of 4 weeks upto 6 months post transplant and patients were treated if

they developed more than 2000 copies of viral DNA. CMV-seronegative recipients of

kidneys from CMV-seropositive donors received valgancyclovir prophylaxis for 6 months.

Follow-Up:

. Patients were followed up regularly during the post transplant period. Routine biochemistry

(CBC,KFT) was done during the follow up (Twice daily for one week, twice/week for 1 month,

once/week for 1 month, once/2 week for 1 month, once a month for 1 year). Information about

all serious adverse events (including possible rejection episodes and opportunistic infections) and
non-serious adverse events believed to be related to study treatment were recorded at each

follow-up visit. If a participant became unwilling or unable to attend the follow-up visits, we

obtained information from them (or their relative or carer) by telephone. Schedule for follow up

was as follows:

Twice/Week for 1 month

Once/Week for 1 month

Once/ 2Week for 1 month

Once a month for 1 year

Definitions of outcome:

Hyperacute graft rejection: Immediate rejection (typically within 10 minutes to 1 hour) of the

kidney on perfusion with recipient blood and absence of major vascular thrombosis.

Acute graft rejection: Presence of any of the following

a. Cellular or humoral rejection proven by kidney biopsy (light microscopy and IF for C4d).
b. Evidence of circulating antibodies to antigens expressed by donor endothelium.
c. An acute increase in S.creatinine (30 percent increase from baseline value) or new /

worsening proteinuria when non immune causes of renal dysfunction have been

excluded. .

Delayed Graft Function: The need for dialysis within the first postoperative week.

Chronic renal allograft nephropathy: Gradual deterioration of graft function as manifested by

slowly rising plasma creatinine concentration, increasing proteinuria, or worsening hypertension.

Graft loss will be defined as:

a) Return to dialysis
b) Retransplant
c) Death with functioning graft

Outcome:

Primary endpoint:
 The primary endpoint of the study will be the development of acute rejection within 06

months post transplant.

Secondary endpoints:

a. Acute Rejection episodes at one year.

b. Allograft survival at 1 year.
c. Patient survival at 1 year.
d. S.Creatinine at 7 days, 6 months and 1 year.

PROFORMA FOR STUDY

UHID. NO

Name: Age:

Sex: M/F Weight:

Blood Group: Transplant Date:

. Contact No:

1. History
 Cause of CKD:

Duration of CKD:

Duration of Haemodialysis / Peritoneal dialysis:

2. Co morbidities
Type 2 DM: HTN:

CAD: Others:

3. Donor details:
Donor: Donor age:
Donor sex:

Donor GFR (DTPA): Rt: Lt:

Donor artery abnormalities:

S. Creatinine: Blood Group:

CMV status:

4. Transplant details

rATG Induction: Done / Not Done

Induction dose of rATG:

Day -1 Day 0

Day 1 Day 2

Total dose:

Ischemia time: Warm - Cold -

 HLA mismatch:

Preformed donor specific antibody:

5. Investigations
Hemoglobin (Hb): TLC:

Platelet Count: Lymphocyte Count:

CMV status:

S. Creatinine :

Week 1/2 1 2 12 24 36 52

TAC level: Day 2: Day 6:

06 month: 12 month:

Proteinuria:

Infections in 1st year: Bacterial / Viral / Fungal

Renal Allograft biopsy report:

6. Outcome:
a. BPAR at 12 months: Present / Absent
b. Acute Rejection episodes: Cellular / Antibody mediated (C4d Positive)
c. Dialysis in 1st week: Done / Not done
d. S. creatinine at 1 year.
e. Allograft survival at 1 year.
f. Patient survival at 1 year:

7. Treatment-
Drugs Duration

1.
 2.

3.

4.

5.

Consent Form

Topic : A study of induction with low dose rabbit anti thymocyte globulin(rATG) in low
risk living donor renal transplant recipients and its correlation with allograft survival

Name of the Patient :

Hospital : Fortis Hospital, Noida

I am free to accept/ refuse to participate in the Study.

 I have been explained the importance/ requirement/ aspects of the study. I
have been given the opportunity to ask questions and replies are given to my
satisfaction.
I have been given and I understand the information regarding the nature,
purpose and duration of the study as well as the procedure involved in the
study including any known or expected inconvenience risk/ discomfort to me.
My medical data shall remain strictly confidential, however I authorize persons
involved in the study to use my medical data for the purpose of this study.

I give my free and full consent to take part into the study as outlined in the
information sheet and the consent form. I have been given a copy of information
sheet and this consent form, by signing this form I have not given up my legal
rights.

Name

Sign

Guardian/ Relative

Consent information sheet

You are invited to take part in research study involving Patients with Kidney
Transplantation at Fortis Hospital, Noida

Kindly read thoroughly the underlying text before consenting for the study.
Purpose

Allograft rejection is an important cause of allograft dysfunction and loss in kidney

transplant patients. The purpose of this study is to study the effectiveness and safety
of induction with low dose rabbit anti thymocyte globulin(rATG) in low risk living
donor renal transplant recipients.

Procedure:

This is a non-interventional study, where subjects enrolled will be observed for renal
dysfunction, infections and rejection episodes during routine follow up post
transplant.

You will be required only once to enter the study as a patient. Enrolment in this study
will not make any difference in treatment protocol for your disease and will also not
disturb your health.

Information obtained will be used only for research purpose and will be kept strictly
confidential.

REFERENCES-
1. Mourad G,Garrigue V, Squiff let JP, et al. Induction versus no induction in renal

transplant recipients with tacrolimus-based immunosuppression. Transplantation 2001;

72: 1050
2. Szczech LA, Berlin JA, Aradhye S, et al. Effect of anti-lymphocyte induction therapy on

renal allograft survival: a meta-analysis. J Am Soc Nephrol 1997; 8:1771.

3. Szczech LA, Berlin JA, Feldman HI. The effect of antilymphocyte induction therapy on

renal allograft survival. A meta-analysis of individual patient-level data. Anti-

Lymphocyte Antibody Induction Therapy Study Group. Ann Intern Med 1998; 128:817.
4. Margaret Bia, MD,1 Deborah B. Adey, MD,2 Roy D. Bloom, et al. KDOQI US

Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney

Transplant Recipients. American Journal of Kidney Diseases, Vol 56, No 2 (August),

2010: pp 189-218
5. Opelz G, Dhler B, Collaborative Transplant Study Report. Influence of time of rejection

on long-term graft survival in renal transplantation. Transplantation 2008; 85:661.

6. Agha IA, Rueda J, Alvarez A, et al. Short course induction immunosuppression with

thymoglobulin for renal transplant recipients. Transplantation 2002; 73:473.

7. Gurk-Turner C, Airee R, Philosophe B, et al. Thymoglobulin dose optimization for

induction therapy in high risk kidney transplant recipients. Transplantation 2008;

85:1425.
8. Stevens RB, Mercer DF, Grant WJ, et al. Randomized trial of single-dose versus divided-

dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

Transplantation 2008; 85:1391.

9. Prville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin

immunosuppressive activity in a nonhuman primate model. Transplantation 2001; 71:460

10. Goggins WC, Pascual MA, Powelson JA, et al. A prospective, randomized, clinical trial

of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant

recipients. Transplantation 2003; 76:798

 11. Wong W, Agrawal N, Pascual M, et al. Comparison of two dosages of thymoglobulin

used as a short-course for induction in kidney transplantation. Transpl Int 2006; 19:629
12. A. Osama Gaber, Arthur J. Matas et al. Antithymocyte Globulin Induction in Living

Donor Renal Transplant Recipients: Final Report of the TAILOR Registry.

Transplantation 2012;94: 00Y00

13. Scientific Registry of Transplant Recipients, Accessed 2011. Available at

http://www.ustransplant.org.
14. M.R. Laftavi et al. Low-Dose Rabbit Antithymocyte Globulin Versus Basiliximab

Induction Therapy in Low-Risk Renal Transplant Recipients: 8-Year Follow-Up.

Transplantation Proceedings 2011, 43, 458461

15. Miller JT, Collins CD, Stuckey LJ, et al. Clinical and economic outcomes of rabbit

antithymocyte globulin induction in adults who received kidney transplants from living

unrelated donors and received cyclosporine-based immunosuppression. Pharmacotherapy

2009; 29:1166
16. Demetra S. Tsapepas et al. Impact of Small Variations in the Delivered Dose of Rabbit

Antithymocyte Induction Therapy in Kidney Transplantation With Early Corticosteroid

Withdrawal,
17. Hammond EB et al. Efficacy of induction therapy on acute rejection and graft outcomes

in African American kidney transplantation. Clin Transplant 2010: 24: 4047 DOI:

10.1111/j.1399-0012.2009.00974

Results :
 Between May 2012 and May 2014, a total of 142 ESRD patients underwent kidney transplant.

31 met exclusion criteria and remaining 111 patients were included in the study. 59 receieved no

induction treatment, 47 receieved low dose ATG and 5 received high dose therapy. Mean age was

37.1 years with no induction group being slightly younger(32.36 years) compared to ATG group

(41.66years). 99 (89.1%) recepients were men and 79 (71.1%) donors were women. 99(89.1%)

recepients were receiving RRT at the time of transplant and the average duration was 6 months in

control group and 7.25 months in ATG group. Hemodialysis was the major form of RRT with

only 1 patient being on CAPD. During the first 6 months after transplantation, the average trough

tacrolimus concentration in participants assigned to low dose ATG based treatment was 7.196

ng/mL and in participants assigned to no induction based treatment it was 7.649 ng/mL. Total

ischemia time was comparable between the two groups (74.73 min in control vs 78.40 min in

ATG group). Significantly more number of recepients were HCV positive in the control

compared to induction group (16.94% vs 6.2%).

A total of 101 patients out of 111 were followed up till primary end point and 10 were

lost to follow up. A total of 23 rejections occurred in the 101 patients analysed corresponding to

an overall rejection rate of 22.7%. . After transplantation, 6 (14.2%) of the 42 participants

allocated to low dose ATG induction group had an episode of biopsy-proven acute rejection

(BPAR) compared with 17 (30.9%) of the 55 patients allocated to control (no induction) group.

The incidence of biopsy proven acute rejection in the control group (29.09%, 6 months and

30.9%, 1 year) and the low dose rATG group (14.2%, 6 months and 14.2%, 1 year) was

significantly more in control group corresponding to a % proportional reduction with ATG-

based treatment. In the control group 16 (94.1%) rejections occurred within first month post

transplant while in low dose ATG group 3(50%) rejections occurred in the first month. There was
no rejection episode between 1 to 6 month in the control group while low dose ATG group had

3(50%) rejections. There were no rejections after 6 months in the low dose ATG group while the

control group had one rejection.

The majority of rejections were antibody mediated in both the groups. Allocation to

ATG induction treatment was associated with fewer antibody-mediated BPAR episodes ( 9.5% vs

21.8%) but there was no between-group difference in cellular BPAR episodes (4.7% vs 5.4%).

Treatment for rejection was based on the severity of rejection. Pulse steroids were given to all

patients with acute rejection. Biopsy was done to determine cause of graft dysfunction. Further

treatment for antibody mediated rejection included plasma exchange, IVIg, ATG and

Bortezomib. Treatment and response is shown in the table. Out of the 16 early rejection in the

control group 7(43.7%) patients had complete recovery of renal function with treatment,

5(31.2%) had partial recovery and 4 (25%) grafts were lost compared to 2(40%) with complete

recovery, 4(60%) with partial recovery and no graft loss due to rejection in the low dose ATG

group. There was no association of rejection with degree of HLA mismatch. Only one patient

had DGF due to ATN post transplant. Death censored graft survival was 3/55(5.4%) compared to

2/42(4.7%)in ATG group at 1 year post transplant, which was not statistically significant.

There was a trend towards lower s. creatinine in ATG group but was not

statistically significant (mean s. creatinine = 1.53 in control group vs 1.41 mg/dl in ATG group

at 6 months). There was no between-group difference in the occurrence of any serious infection

(defined as an opportunistic infection or one requiring admission to hospital). Overall, the

occurrence of opportunistic infections did not differ between groups. The occurrence of any

cytomegalovirus (CMV)/ BK Virus infections also did not differ between groups. Nearly all the

patients were D+ R- serostatus for CMV except one who was D+ R-. 3 patients in low dose ATG
group developed CMV infection and only one out of these 3 developed symptomatic CMV

disease. All three patients received Valgancyclovir treatment as they had more than 2000 DNA

copies. Post-transplant lymphoproliferative disorder(PTLD) did not occur during the follow up

period in any patient. . An additional cost of approximately Rs. 100,000/patient was incurred by

the rATG group.

There was no between-group diff erence in the occurrence of graft failure in control
group(10.9%)compared to ATG group (9.3%) at 1 year post transplant. Rejection caused graft
loss in 7.2% patiMortality was also not statistically different among the two groups at 1 year.
Post transplant infection/ sepsis was the most common cause of death.

This observational study was performed in intermediate immunologic risk live donor renal
transplants to assess rATG efficacy in patients on tacrolimus, mycophenolate, and prednisolone
immunosuppression. A total of 34 patients on rATG induction were compared to risk matched 48
controls at the end of 6 and 12 months post-transplant. An additional cost of approximately Rs.
100,000/patient was incurred by the rATG group. The incidence of biopsy proven acute rejection
in the control group (12.5%, 6 months and 20.5%, 1 year) and the rATG group (13%, 6 months
and 18.9%, 1 year) was similar. The incidence of infections was similar and none of the patients
had a malignancy

We reviewed participants at time of discharge from hospital and at 1, 3, 6, 9, and 12 months after

transplantation. At each follow-up visit, we measured blood pressure and weight, and obtained

blood and urine samples for local analysis of creatinine, full blood count, tacrolimus

concentration, and urine protein-to-creatinine ratio

The incidence of biopsy-proven acute rejection (including cellular and antibody-mediated

rejection) during the first 6 months after transplantation (the primary outcome) was

estimated to be about . patients on tacrolimus, mycophenolate, and prednisolone

immunosuppression. A total of 34 patients on rATG induction were compared to risk matched 48

controls at the end of 6 and 12 months post-transplant. An additional cost of approximately Rs.
100,000/patient was incurred by the rATG gro For time-to-event analyses, we used Cox

regression methods 16 to calculate event rate ratios and 95% CIs, and we estimated two-sided p

values using logrank

methods (except for delayed graft function, which we analysed using logistic regression.

Analysis of biopsy-proven acute rejection during the first year after transplantation showed

that the benefit of low dose ATG based treatment arose during the first few weeks and was

maintained at 1 year no between-group difference in the occurrence of any serious infection

(defined as an opportunistic infection or one requiring admission to hospital; table 3). Overall,

the occurrence of opportunistic infections did not differ between groups (table 3). The

occurrence of any cytomegalovirus (CMV) infections also did not differ between groups

Total patients between May 12 to May 14

= 142

Exclusion criteria = 31, Included = 142- 31 = 111

31 = Simulect (23) + Deceased donor (2) + liver-

kidney transplant (2 ), Age < 18 yrs(1)
 No Induction Low dose High dose
n = 59 ATG n = 47 ATG n= 05

Lost to follow = Lost to follow = Lost to follow =

4 55 analysed 5 42 analysed 1 4 analysed

Rejections at 6 mth= 16 Rejections at 6 mth= 6 No rejections

(29%). AMR = 11(20%),
ACR = 3 (5.4%), Mixed = 2
(3.6%)
S. Creatinine at 6/ 12Mth =
1.53/1.51 mg/dl
Graft failure at 12 mth =
6(10.9%)
Death censored graft failure =
3/55(5.4%)
Death (Any cause) = 5
(7.2%)
(14.2%) AMR = 4(9.5%),
ACR = 2(4.7%), Mixed = nil Death = 1
Recepient Age = 46 yrs
S. creatinine at 6/12 Mth =
1.41/1.47 mg/dl
Graft failure at 12 mth = 4
(9.5%)
Death censored graft failure =
2/42(4.7%)
Death (Any cause) = 2 (4.7%)
Recepient Age = 41.66 yrs

Recepient Age = 32.36 yrs Recepient Age = 45.2 yrs

Donor age = 45.25 yrs RRT Duration = 7.25 mth

RRT Duration = 6 mth