induction therapy commonly refers to the administration of antibodies against specific or multiple antigenic targets of immune cells in the immediate peri - operative period .
these antibodies have largely been used to provide immunosuppression at the time of antigen presentation , during the initial period after solid organ transplantation , with the purpose of reorienting the immune system by depleting potentially alloreactive immune cells .
several meta - analyses have demonstrated that induction therapy improves renal graft outcome compared with conventional therapy .
antilymphocyte antibodies have a beneficial effect on 2-year allograft survival , and non - depleting antibodies , such as the anti - cd25 antibodies basiliximab and daclizumab , reduce acute rejection rate [ 36 ] . moreover
, induction drugs play a key role in the promising corticosteroid or calcineurin - inhibitor minimization strategies .
the frequency of use of the different induction drugs has varied markedly over the last 15  years . while in the early 1990s
the majority of us kidney transplant recipients did not receive induction therapy , in 2004 nearly 72% of recipients received some kind of antilymphocyte drug .
currently , thymoglobulin is the most frequently used ( 37% ) induction agent in the usa , and anti - cd25 antibodies are used only rarely . apart from the usa ,
data from the australia and new zealand dialysis and transplant ( anzdata ) registry showed a decline in okt3 and polyclonal antibody use and an increase in the prescription of anti - cd25 antibodies to 57.1% in 2001 .
non - serial studies provide data about induction use in some asian centres ( 18.4% ) , international registries ( 37.7% )   and one south american centre ( 36% ) .
one of the aims of our study was to describe the trends in induction use from 1990 to 2002 in spain and the differences in use among centres .
the high rate of variation between countries and centres in induction use revealed not only differences between transplant populations but also differences in indication .
other centres use lymphocyte - depleting agents for high - risk patients and non - depleting agents for low - risk patients . the lack of common indications for induction therapy would suggest that it is not well known which patients should receive it and what induction drug must be prescribed
. the benefits of using induction must be weighed against the potential risk of infection and malignancy .
commonly , induction is used in patients with a higher rejection risk ( african - american , highly sensitized patients , patients undergoing re - transplantation ) , a higher delayed graft function risk ( longer cold ischaemia time , expanded criteria donors , donors after cardiac death ) or in patients under minimization immunosuppressive strategies .
the second purpose of our study was to know in which patients in spain induction was prescribed and the differences in use between polyclonal antibodies and anti - cd25 antibodies . over the last few years ,
focus on kidney transplantation has shifted towards long - term graft survival due to the improvements in short - term graft survival .
the effect of induction antibodies over long - term graft survival is controversial . by means of a meta - analysis of individual patient - level data , szczech et al .
showed a benefit of induction at 2  years in all patients and even at 5  years in recipients with panel reactive antibodies ( pra ) 20% . a single - centre study comparing polyclonal antibody induction against no induction demonstrated that induction improved graft survival only during the first post - transplant year and did not exert its effect further .
antibody induction is also associated with an elevated risk for cardiovascular death , infection - related death and malignancy - related death .
data about the long - term effect of induction on patient and graft survival are scarce .
we conducted a retrospective cohort study with patients receiving a kidney allograft in spain over four different years ( 1990 , 1994 , 1998 and 2002 ) .
only adult patients ( 18  years ) , receiving a single kidney and remaining alive with a functioning graft at the end of the first post - transplant year were included in the study .
the following data were recorded for each patient at the time of transplantation and during hospitalization until discharge by chart review : age and gender of the donor and the recipient , source of the organ ( living or deceased donor ) , cause of donor death , primary kidney disease , recipient body mass index , peak and current pra , number of transplants , time on renal replacement therapy , mismatches , presence of hepatitis c antibodies in the recipient , and cold ischaemia time .
graft and patient survival , delayed graft function , acute rejection , first - year creatinine and first - year hypertension were also collected from the clinical charts .
delayed graft function was defined as the need for dialysis within the first week after transplantation .
the diagnosis of acute rejection was defined according to the criteria of each centre based on clinical and histological data .
arterial hypertension was defined as blood pressure more than 140/90  mmhg or need for antihypertensive therapy .
induction therapy was defined when the patient received polyclonal antibodies ( alg , atg , atgam , thymoglobulin ) , okt3 monoclonal antibodies or anti - cd25 monoclonal antibodies ( basiliximab , daclizumab ) .
other induction drugs were used under clinical trials and were excluded from the analysis . during the study period ,
there were inadequate data with respect to induction therapy ( data absence or duplicate ) , or they received different induction drugs for clinical trials .
medical record review was performed by a transplant physician at each centre taking part in the study according to spanish law with reference to clinical data confidentiality ( spanish official bulletin , boe no .
comparison between variables was made by using student s t - test for numerical values and chi - square test for categorical data .
stepwise multiple regression analysis was used to select independent risk factors for receiving induction therapy among parameters selected by univariate analysis .
independent risk factors for graft loss were studied by means of cox s regression analysis .
there were significant differences in the percentages of transplant patients that received induction therapy ( 25.7% in 1990 , 40.7% in 1994 , 27.1% in 1998 and 37.2% in 2002 , p < 0.0001 ) but without a clear trend .
similarly , there were significant differences in the percentages of transplant patients under polyclonal antibodies ( 19.9% in 1990 , 31.1% in 1994 , 17.0% in 1998 and 9.2% in 2002 , p < 0.0001 ) . during the study period , there was a significant reduction in the number of patients receiving okt3 ( 4.9% in 1990 , 9.3% in 1994 , 5.0% in 1998 and 1.0% in 2002 , p < 0.0001 ) .
by contrast , a significant increase in the percentages of patients treated with anti - cd25 antibodies was found ( 1.3% in 1990 , 0.9% in 1994 , 5.6% in 1998 and 27.2% in 2002 , p < 0.0001 ) .
polyclonal antibodies in white , okt3 in black and anti - cd25 antibodies in grey . throughout the study period
, there was great variability in the use of induction therapy among the different spanish transplant centres .
induction use ranged from 1.6% to 98.1% ( mean 36.4% ) for any patient in each centre .
polyclonal antibody use ranged from 0% to 78% ( mean 21.1% ) and anti - cd25 antibodies from 0% to 73% ( mean 9.5% ) . nearly half ( 48.5% ) of the centres
used induction therapy in less than 25% of patients , while 24.2% of the centres used induction from 25% to 50% of patients and 27.3% of the centres in more than half their transplant recipients . from 1990 to 2002 , the percentages of centres using induction therapy in less than 25% of their patients fell from 62.9% to 39.3% , while the centres using induction therapy with between 25% and 50% of their recipients increased from 3.6% to 32.1% .
nearly a third of the centres treated more than 50% of their patients with induction drugs ( 33.3% in 1990 and 28.6% in 2002 ) .
most of the centres that treated more than 50% of their transplant patients with induction therapy in 1990 were using polyclonal antibodies ( 86% ) . in 2002 , these same centres used induction treatment in 56% of patients , but only 18% of them received polyclonal antibodies , while 38% received anti - cd25 antibodies ( p < 0.01 ) .
on the other hand , centres that used induction therapy in less than 25% of their patients ( 3% ) in 1990 increased the use of induction to more than a quarter of the patients ( 27% ) and used anti - cd25 antibodies ( 18% ) more frequently than polyclonal antibodies ( 9% ) . the only donor characteristic related in univariate analysis with a higher rate of induction prescription was donor age ( table  1 ) .
we found no differences in the use of induction according to donor sex , death cause or donor status ( deceased vs live - donor ) .
donor and recipient characteristics of transplant patients receiving induction therapy vs those not receiving rrt , renal replacement therapy ; cva , cerebro - vascular accident .
recipient characteristics related with a higher rate of induction therapy were recipient age , the title of pra , the length of renal replacement therapy , the number of mismatches , the number of transplants and recipient diabetes ( table  1 ) .
after multivariate analysis , patients who received induction more frequently were those older than 60  years ( rr 1.28 , 95% ci 1.031.58 , p = 0.0211 ) , with more than 15% of pra ( rr 1.74 , 95% ci 1.322.30 , p = 0.0001 ) , receiving a second or more transplant ( rr 1.47 , 95% ci 1.111.95 , p = 0.0061 ) , with more mismatches ( rr 1.20 , 95% ci 1.121.28 , p < 0.001 ) and diabetic ( rr 1.54 , 95% ci 1.132.09 , p = 0.0055 ) . in 2002 , a higher number of patients under induction therapy received anti - cd25 antibodies ( 323 ) than polyclonal antibodies ( 104 ) .
patients treated with polyclonal antibodies were younger , had a higher rate of current and peak pra and were more frequently re - transplants ( table  2 ) .
characteristics of patients receiving polyclonal antibodies or anti - cd25 antibodies in 2002 rrt , renal replacement therapy ; cva , cerebro - vascular accident . considering a follow - up period of 15  years ( since 1990 ) and censoring patients with functioning graft but with a shorter follow - up ,
the average time of graft survival in patients who were treated with induction therapy has been significantly higher than those who were not ( 14.092  years ; ic95%=[13.76714.416 ] vs 13.595 ; ic95%=[13.33813.852 ] ; p value = 0.035 ) ( figure  2 ) . likewise ,
14% of patients who received induction and 15.6% of patients who did not receive induction lost their grafts . after adjusting for delayed graft function , acute rejection , first year creatinine , pre - transplant pra , first year hypertension and receptor age , the use of induction therapy remained significant as a protective factor for graft survival ( hr 0.686 , 95% ci 0.5870.801 , p < 0.001 ) .
by contrast , induction therapy was neither a risk nor a protective factor for patient survival ( log rank test p = 0.072 ) .
this advantage over graft survival related with induction therapy was not the same for all groups of patients .
patients younger than 55  years who received induction therapy had a significantly higher allograft survival than the others who did not receive induction treatment ( p = 0.008 ) . also , 15.1% of the patients who received induction therapy had graft loss vs 17.6% without induction .
there were , however , no graft survival advantages in those patients older than 55  years who received induction therapy ( graft loss after induction therapy 10.5% vs 10.3% without induction , p = 0.758 ) .
patients with current pra lower than 20% benefited more by receiving induction therapy ( graft loss after induction therapy 13.2% vs 16.0% without induction , p = 0.014 ) . on the other hand ,
patients with current pra equal to or higher than 20% showed no advantage for being treated with induction ( graft loss after induction therapy 20.5% vs 27.1% without induction , p = 0.224 ) .
there were significant differences in the percentages of transplant patients that received induction therapy ( 25.7% in 1990 , 40.7% in 1994 , 27.1% in 1998 and 37.2% in 2002 , p < 0.0001 ) but without a clear trend .
similarly , there were significant differences in the percentages of transplant patients under polyclonal antibodies ( 19.9% in 1990 , 31.1% in 1994 , 17.0% in 1998 and 9.2% in 2002 , p < 0.0001 ) . during the study period , there was a significant reduction in the number of patients receiving okt3 ( 4.9% in 1990 , 9.3% in 1994 , 5.0% in 1998 and 1.0% in 2002 , p < 0.0001 ) .
by contrast , a significant increase in the percentages of patients treated with anti - cd25 antibodies was found ( 1.3% in 1990 , 0.9% in 1994 , 5.6% in 1998 and 27.2% in 2002 , p < 0.0001 ) .
polyclonal antibodies in white , okt3 in black and anti - cd25 antibodies in grey .
throughout the study period , there was great variability in the use of induction therapy among the different spanish transplant centres .
induction use ranged from 1.6% to 98.1% ( mean 36.4% ) for any patient in each centre .
polyclonal antibody use ranged from 0% to 78% ( mean 21.1% ) and anti - cd25 antibodies from 0% to 73% ( mean 9.5% ) . nearly half ( 48.5% ) of the centres
used induction therapy in less than 25% of patients , while 24.2% of the centres used induction from 25% to 50% of patients and 27.3% of the centres in more than half their transplant recipients . from 1990 to 2002 , the percentages of centres using induction therapy in less than 25% of their patients fell from 62.9% to 39.3% , while the centres using induction therapy with between 25% and 50% of their recipients increased from 3.6% to 32.1% .
nearly a third of the centres treated more than 50% of their patients with induction drugs ( 33.3% in 1990 and 28.6% in 2002 ) .
most of the centres that treated more than 50% of their transplant patients with induction therapy in 1990 were using polyclonal antibodies ( 86% ) . in 2002 , these same centres used induction treatment in 56% of patients , but only 18% of them received polyclonal antibodies , while 38% received anti - cd25 antibodies ( p < 0.01 ) .
on the other hand , centres that used induction therapy in less than 25% of their patients ( 3% ) in 1990 increased the use of induction to more than a quarter of the patients ( 27% ) and used anti - cd25 antibodies ( 18% ) more frequently than polyclonal antibodies ( 9% ) .
the only donor characteristic related in univariate analysis with a higher rate of induction prescription was donor age ( table  1 ) .
we found no differences in the use of induction according to donor sex , death cause or donor status ( deceased vs live - donor ) .
donor and recipient characteristics of transplant patients receiving induction therapy vs those not receiving rrt , renal replacement therapy ; cva , cerebro - vascular accident .
recipient characteristics related with a higher rate of induction therapy were recipient age , the title of pra , the length of renal replacement therapy , the number of mismatches , the number of transplants and recipient diabetes ( table  1 ) .
after multivariate analysis , patients who received induction more frequently were those older than 60  years ( rr 1.28 , 95% ci 1.031.58 , p = 0.0211 ) , with more than 15% of pra ( rr 1.74 , 95% ci 1.322.30 , p = 0.0001 ) , receiving a second or more transplant ( rr 1.47 , 95% ci 1.111.95 , p = 0.0061 ) , with more mismatches ( rr 1.20 , 95% ci 1.121.28 , p < 0.001 ) and diabetic ( rr 1.54 , 95% ci 1.132.09 , p = 0.0055 ) . in 2002 ,
a higher number of patients under induction therapy received anti - cd25 antibodies ( 323 ) than polyclonal antibodies ( 104 ) .
patients treated with polyclonal antibodies were younger , had a higher rate of current and peak pra and were more frequently re - transplants ( table  2 ) .
characteristics of patients receiving polyclonal antibodies or anti - cd25 antibodies in 2002 rrt , renal replacement therapy ; cva , cerebro - vascular accident .
considering a follow - up period of 15  years ( since 1990 ) and censoring patients with functioning graft but with a shorter follow - up , the average time of graft survival in patients who were treated with induction therapy has been significantly higher than those who were not ( 14.092  years ; ic95%=[13.76714.416 ] vs 13.595 ; ic95%=[13.33813.852 ] ; p value = 0.035 ) ( figure  2 ) . likewise ,
14% of patients who received induction and 15.6% of patients who did not receive induction lost their grafts . after adjusting for delayed graft function , acute rejection ,
first year creatinine , pre - transplant pra , first year hypertension and receptor age , the use of induction therapy remained significant as a protective factor for graft survival ( hr 0.686 , 95% ci 0.5870.801 , p < 0.001 ) .
by contrast , induction therapy was neither a risk nor a protective factor for patient survival ( log rank test p = 0.072 ) .
this advantage over graft survival related with induction therapy was not the same for all groups of patients .
patients younger than 55  years who received induction therapy had a significantly higher allograft survival than the others who did not receive induction treatment ( p = 0.008 ) . also , 15.1% of the patients who received induction therapy had graft loss vs 17.6% without induction .
there were , however , no graft survival advantages in those patients older than 55  years who received induction therapy ( graft loss after induction therapy 10.5% vs 10.3% without induction , p = 0.758 ) . patients with current pra lower than 20% benefited more by receiving induction therapy ( graft loss after induction therapy 13.2% vs 16.0% without induction , p = 0.014 ) .
on the other hand , patients with current pra equal to or higher than 20% showed no advantage for being treated with induction ( graft loss after induction therapy 20.5% vs 27.1% without induction , p = 0.224 ) .
unlike us data , we can not find a trend toward increasing use of induction drugs in kidney transplantation between 1990 and 2002 in spain .
moreover , such use is quite lower than the reported induction use in the usa ( from 46% in 1995 to 72% in 2004 ) .
it seems that induction therapy has been used at a higher rate in spain beyond 2002 , but we can not conclude this from our data . clearly
, the use of the monoclonal antibody okt3 has waned in spain progressively ( 1.0% in 2002 ) , similar to that reported by us and anzdata registries . nowadays , depleting induction therapy
is based on polyclonal antibodies in spain , the usa , australia and new zealand . from the brennan et al .
report comparing thymoglobulin with atgam in 1999 , thymoglobulin has become the preferred polyclonal agent , although this finding could not be demonstrated in our study since that polyclonal induction use registry includes different agents . all over the world , non - depleting anti - cd25 monoclonal antibodies are being used in a higher percentage of patients .
anti - cd25 antibodies were used in 27.2% of patients in 2002 in spain , in 57.1% in 2005 in australia and new zealand and in 21% in 2004 in the usa .
this increasing use can be attributed both to initial studies [ 2022 ] and to further meta - analysis that have shown that anti - cd25 antibodies reduce acute rejection rates compared with placebo [ 46 ] .
together with their efficiency reducing rejection rates , the costs with anti - cd25 are lower compared to transplant without induction . as a result of these data ,
the use of induction antibodies varies between centres , although there are few reported data about this issue .
the wide range of induction use ( 1.698.1% ) , polyclonal antibody use ( 078% ) and anti - cd25 use ( 073% ) in spain can only be partly explained by differences in population characteristics in spanish centres .
some such centres in spain have a very high rate of diabetic recipients or re - transplants
. however , lack of consensus about specific indications seems the main cause of this heterogeneity . the global spanish trend to use induction drugs in a higher rate of patients at each centre , at more similar rates among the different centres and mainly anti - cd25 antibodies , would indicate that induction indications will be more homogeneous in the future .
no previous report has analysed which kidney recipients have received induction therapy in such a high number of patients .
for example , nol et al . defined this kind of patient as having one or more of the following risk factors : a current pra  30% , a peak pra  50% , scheduled for a second transplantation when the first graft was lost to rejection within 2  years or receiving a third or fourth kidney graft .
designed their trial to include patients at risk for both acute rejection and delayed graft function , taking into account cold ischaemia time , donor age , non - heart - beating donor , high - dose inotropic support of donor , repeated transplantation , current pra > 20% , black race and mismatches . in our retrospective study , induction therapy was used in older recipients , with a higher pra rate , receiving a second or more transplantation , with more mismatches and diabetic . among studied variables , no donor characteristic was related with induction indication .
some of these recipient variables were related with a higher immunological risk for acute rejection , such as pra , re - transplantation and mismatches , while the recipient age and diabetes are more related with the risk for delayed graft function and the intention to use steroid or calcineurin - inhibitor minimization strategies .
surprisingly , the use of induction therapy in the usa was no different among groups with varying pra .
by contrast , most of the us patients on steroid - avoidance regimens received induction drugs . as several meta - analyses have shown that induction therapy improves kidney transplant outcomes in a cost - effective way compared with no induction ,
a possible future scenario is that induction therapy will be used in all kidney transplants [ 36,23 ] . in this case
, the doubt will be what induction we must use ( polyclonal antibodies , mainly thymoglobulin , or anti - cd25 antibodies ) .
several trials including low - immunological - risk patients have found similar rates of acute graft rejection and graft and patient survival , with higher rates of cytomegalovirus infection with polyclonal antibodies compared with anti - cd25 antibodies . in high - risk patients ,
the rate of acute rejection was greater in those patients treated with anti - cd25 antibodies , but graft and patient survival was the same at the first and fifth years .
our study can not allow us to compare outcomes of patients receiving polyclonal antibodies vs anti - cd25 antibodies , but we analysed which kidney graft recipients were prescribed either of them .
thus , spanish centres used polyclonal antibodies instead of anti - cd25 in patients with a higher acute rejection risk ( high pra and re - transplants ) but with a lower infection risk due to their younger age .
it has been difficult to know the effect of induction therapy on long - term graft survival . in a single - centre study ,
1-year graft survival was better in patients receiving polyclonal induction ( 93% vs 79% ) , but no difference was observed from the second to the 20th year in graft survival .
a meta - analysis of seven randomized trials comparing lymphocyte - depleting induction with no - induction therapy showed a statistically significant improvement in 2-year graft survival in patients treated with induction drugs .
another meta - analysis including 17 trials and 2786 patients found no differences in graft loss at the first and third years between those patients treated and those not treated with anti - cd25 antibodies . in a recent retrospective usrds analysis between 1997 and 2004 ,
gill et al . reported no differences in 1- and 5-year graft survival in low - risk renal transplant recipients receiving polyclonal antibodies vs no - induction therapy .
the benefits of using induction therapy must be weighed against the potential risk of overimmunosuppression , including the risks of infection and malignancy that may occur years after the induction use .
lymphocyte - depleting induction is related with a significantly increased risk for early deaths within 6  months and after 6  months post - transplantation in relation with infection , malignancy and cardiovascular problems .
however , patients with a kidney surviving more than 1  year who received induction therapy in spain showed a significantly better long - term graft survival with the same patient survival than those not treated with induction drugs .
induction therapy exerts its protective role over graft survival independently of other confounding factors , such as acute rejection .
this result can not be compared with previous studies due to the fact that we analysed only kidneys functioning beyond the first year .
the high number of patients in our study allows us to assert that an immunosuppressive regimen including induction drugs can improve long - term graft survival , this favourable effect being different according to which groups received treatment . in our study , recipients younger than 55  years and with low pra benefited more from receiving induction therapy . in conclusion , from 1990 to 2002 , the use of induction therapy in spain changed , with a progressive reduction in the use of okt3 and an increasing use of anti - cd25 antibodies .
there were great differences in the rate of induction use among the different centres , although with a common trend to its use in more patients .
induction therapy was mainly prescribed in patients with a higher rejection risk ( higher pra titres and mismatches and re - transplants ) and/or needing calcineurin - inhibitor or steroid minimization regimens to prevent delayed graft function and other secondary effects ( older and diabetic recipients ) .
 background . 
 the use of induction drugs has increased markedly over the last 15  years in the usa , but there are few data about their use in other countries . moreover , there are not enough data about when they are indicated and their long - term effects . 
 the aim of our study was to know the rates of use and the drugs used as induction therapy , in which patients they were prescribed and the long - term graft survival effect in spain.methods . 
 we conducted a retrospective cohort study with adult patients ( 4861 ) receiving a kidney allograft in spain over four different years ( 1990 , 1994 , 1998 and 2002 ) with a functioning graft at the end of the first post - transplant year . 
 induction therapy was defined as when the patient received polyclonal antibodies , okt3 monoclonal antibodies or anti - cd25 monoclonal antibodies.results . from 1990 to 2002 , the use of induction therapy in spain changed , with a progressive reduction in the use of okt3 and an increasing use of anti - cd25 antibodies . 
 there were great differences in the rate of induction use from one centre to another , although with a common trend to greater use at each centre . 
 induction therapy was mainly prescribed in patients with a higher rejection risk ( higher panel reactive antibody ( pra ) titres and mismatches and re - transplants ) and in older and diabetic recipients . 
 lastly , patients who were treated with induction therapy had significant higher allograft survival than those who did not ( p value = 0.035).conclusions . 
 the use of induction therapy in spain has changed , with an increasing use of monoclonal antibodies in recent years . 
 induction therapy has a protective role in long - term graft survival . 
Introduction
Materials and methods
Results
Year of transplantation
Transplant centre
Induction indication
Induction results
Discussion