Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Renal disease

Most diseases that cause renal failure fall into five categories: systemic disease, glomerulonephritis, hypertension, obstruction and genetic disease (Table 1), with diabetes mellitus causing around 20% of all renal disease. 3

When established renal failure is reached, people become tired, nauseated, lose their appetite and cope less well both physically and mentally. The signs of established renal failure include fluid retention (shown as swollen ankles or breathlessness), itching, pallor and raised blood pressure. These symptoms are accompanied by falling haemoglobin levels and abnormality of biochemical markers, for example serum urea, serum creatinine and potassium. When someone reaches this point they will need RRT within weeks or months to prevent death. Treatment will continue for the rest of their lives.

Survival, acute rejection and graft loss after transplantation

Various factors may influence patient survival after kidney transplantation (including factors related to the donor and to the patient). For example, the type of donor can influence patient survival, with recipients of a kidney transplant from an ECD having inferior survival outcomes compared with recipients of standard criteria donor kidneys. However, those from an ECD will still have significantly better survival outcomes than people on waiting lists who remain on HD. 4,5

In people who survive transplantation, acute rejection (AR) may occur when the immune response of the host attempts to destroy the graft, as the graft is deemed foreign tissue. 2 AR is treated using changes to the immunosuppressive regimen (increasing doses or switching treatments). Untreated AR will ultimately result in destruction of the graft. However, high levels of immunosuppression may also increase the risk of other infections and malignancy. 2 AR is primarily measured after a biopsy and is graded according to Banff criteria (grades I–III). The gradings are as follows: grade I, moderate to severe mononuclear cell interstitial infiltrate and moderate tubulitis; grade II, severe tubulitis and/or intimal arteritis; and grade III, transmural arteritis. 6 Incidences of ARs after a transplant are included in this appraisal; however, the treatment for AR is outside the scope of this appraisal.

In addition to ARs affecting the survival of the graft, other reasons that may facilitate graft loss include blood clots, narrowing of an artery, fluid retention around the kidney, side effects of other medications and recurrent kidney disease (www.kidney.org). A major cause of long-term graft loss is chronic allograft nephropathy, an ill-defined process, characterised clinically by progressive deterioration in graft function (GRF), proteinuria and hypertension, and pathologically by changes on biopsy. Chronic allograft nephropathy is a consequence of immunological and non-immunological injury. Immunological factors include human leucocyte antigen (HLA) matching, episodes of AR and suboptimal immunosuppression. Important non-immunological factors implicated are donor organ characteristics, delayed graft function (DGF), recipient-related factors, hypertension and hyperlipidaemia. Recently, the acute and chronic toxicity of calcineurin inhibitors (CNIs) has also been implicated. 7 People with high titres of preformed circulating anti-HLA antibodies – which may come about as a result of underlying illness, previous transplantation, previous pregnancy or multiple blood transfusions – are at high risk of chronic rejection. 8

It is important to note that failing to adhere (or comply) with the immunosuppression regimen prescribed after a kidney transplant will also significantly increase the risk of an ARs and/or graft loss. 9 If the kidney is lost then, ultimately, the patient will need to return to dialysis where quality of life is lower and overall costs are higher. 2

Significance for patients

To a person suffering from ESRD the opportunity to have a kidney transplant is literally a matter of life or death. In the year 2013–14, in the UK, 239 people died while on the active and suspended waiting lists for kidney transplantation; 518 people were removed from the list because they were no longer fit enough, most of whom would go on to die. 12 Encouragingly, over the last 5 years there has been a decline in the number of people waiting for a kidney transplant (Figure 3). This decline has primarily been attributed to an increase in the number of transplants being performed each year, as the number of people joining the list each year has remained relatively stable. 12 Although this is encouraging, figures from people registered between April 2007 and March 2011 indicated that the median wait time for a kidney-only transplant in the UK was over 3 years (1114 days) with a 95% confidence interval (CI) of 1091 to 1137 days. 13

FIGURE 3.

Number of donors, transplants and people on the active transplant list from 1 April 2004 to 31 March 2014. Decreased donor kidney programme in the UK, 1 April 2004 to 31 March 2014. Number of donors, transplant and patients on the active transplant list at 31 March. Source: Organ Donation and Transplantation Activity Report 2013/2014, NHSBT. 12 Reproduced with permission.

Although kidney transplantation relieves the person with ESRD from lengthy dialysis, the strict regimen of immunosuppressant medication required may produce unpleasant side effects, including possible skin cancer, crumbling bones, fatigue, body hair growth, swollen gums and weight gain. 14 Nevertheless, a large number of studies have similarly documented, using a variety of instruments, the clear quality-of-life improvements of having a functioning kidney transplant compared with being on dialysis. 15–27 Overbeck et al. ,26 for example, compared the quality of life of those who had received a kidney transplant with those dialysing and on the waiting list, and they found that, when measured with the Short Form questionnaire-36 items (SF-36), people who had received a transplant reported better physical functioning, perception of general health, social functioning and overall physical component than those still dialysing, although these scores did not match those of the general population (Table 4).

Acute rejection is common in the first year after kidney transplantation, and treatment of AR involves a more intensive drug treatment than standard maintenance regimens, which, in turn, increases the possibility of unpleasant side effects. The treatment for AR is outside the scope of this appraisal. Should a graft be lost, people face another wait for transplantation (if appropriate), which may be even longer owing to sensitisation to the mismatched HLA on the failed donor kidney. Furthermore, they will need to undergo dialysis while waiting for transplantation or for life when transplantation is not possible. This, in effect, means that people may be in a worse position from when they started their treatment, but with the added psychological and physical burden from having undergone transplantation. Indeed, many people will develop depression following the loss of a graft. 28

The impact on people of returning to dialysis (with regards psychological burden of graft failure and going back to a previous treatment modality) is scarcely documented, but necessarily includes the impact of being on dialysis per se: dialysis is time-consuming and may affect employment, education, normal family life and require changes in diet and fluid intake. Common side effects to dialysis (either HD or PD) include fatigue, low blood pressure, invasive staphylococcal infections, muscle cramps, itchy skin, peritonitis, hernia and weight gain (www.nhs.uk). Quality of life is lower on dialysis than the general population29 and declines over time as the patient remains on dialysis. 30

Significance for the NHS

Treatment for ESRD has been deemed resource intensive for the NHS, as current costs have been estimated to utilise 1–2% of the total NHS budget to treat 0.05% of the population. 10 Data from the Department of Health estimated that in 2008–9 the total expenditure on ‘renal problems’ in England was £1.3B, representing 1.4% of the NHS expenditure. An economic evaluation of treatments for ESRD by de Wit et al. 31 showed that transplantation is the most cost-effective form of RRT with increased quality of life and independence for people.

It is projected that with an increasingly elderly and overweight population the demand for RRT will increase, with a consequent pressure on services providing renal units and other health-care providers dealing with comorbidities. Increased resources may be needed for dialysis, surgery, pathology, immunology, tissue typing, histopathology, radiology, pharmacy and hospital beds. Demand is likely to be particularly significant in areas where there are large South Asian, African and African Caribbean communities, and in areas of social deprivation, in which people are more susceptible to kidney disease. 32

Data from the NHS Standard Contract for Adult Kidney Transplant Service indicated that the cost for the first year of care following a kidney transplant is approximately £17,000 and then £5000 for every subsequent year. Conversely, the cost of dialysis is approximately £30,800 per year. 33 However, should a graft be lost following a transplant, the NHS would incur increased costs from either the patient returning to dialysis or requiring a replacement renal transplant (in comparison with successful maintenance of the kidney graft). Similarly, each AR episode would incur increased costs because of the changes made to the immunosuppression regimen to treat the rejection.

Management of end-stage renal disease

End-stage renal disease is primarily managed by RRT. The patient pathway leading to RRT for those with ESRD can be seen in Figure 5. The distribution of people on differing RRTs in the UK as of 31 December 2012 is shown in Figure 6.

FIGURE 5.

The care pathway for RRT. Source: The National Service Framework for Renal Services – Part 1: Dialysis and Transplantation. 36

FIGURE 6.

Treatment modality in prevalent RRT adults on 31 December 2012 in the UK. Source: The Sixteenth Annual report from the UK Renal Registry. 3 APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis. Source: Annual Report on Kidney Transplantation, Report for 2013/2014, NHS Blood and Transplant. 11 Reproduced with permission. The data reported here have been supplied by the UK Renal Registry of the Renal Association. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the UK Renal Registry or the Renal Association.

Management of kidney transplant

If transplantation is the chosen method of RRT for a patient with ESRD then, from the perspective of person receiving the transplant, there are three main service provision steps required for the management of the transplant.

The first of these steps is organ procurement, which includes the identification of potential donors, assessment of donor suitability, determination of donor brain death (where applicable) and medical management of the donor. Donor–recipient compatibility includes an assessment on HLA matching. HLAs are carried on cells within the body, enabling the body to distinguish between ‘itself’ and ‘non-self’, which should be attacked. The closer the HLA matching, the less vigorously the body will attack the foreign transplant; consequently, the chances of graft survival are improved. HLA mismatch refers to the number of mismatches between the donor and the recipient at the A, B and DR loci, with a maximum of two mismatches at each locus. 11 However, it should be noted that because of improvements in immunosuppressants, the significance of HLA matching has diminished. 37

The second step is the provision of immunosuppressive therapy. Immunosuppressants are the drugs taken around the time of, and following, an organ transplant. They are aimed at reducing the body’s ability to reject the transplant, and thus at increasing patient and graft survival and preventing acute and/or chronic rejection (while minimising associated toxicity, infection and malignancy). Immunosuppressants are required in some form for all kidney transplant recipients (KTRs) except, potentially, when the donor is an identical twin. The immunosuppressive drugs can be divided into induction and maintenance drugs. Induction drugs are powerful antirejection drugs that are taken at the time of transplantation and close after, when the risk of rejection is highest. Maintenance drugs are less powerful antirejection drugs that are used as both initial and long-term maintenance therapy.

The final service provision step is short- and long-term follow-up following transplantation. This step involves looking for indications of any kidney graft dysfunction and/or other complications. Complications fall into three categories:

• medical follow-ups to monitor for, and treat, rejections; nephrotoxicity of CNIs; and recurrence of the native kidney diseases

• anatomical complications of surgery, including renal artery thrombosis, renal artery stenosis, urine leaks from disruption of the anastomosis, ureteral stenosis and obstruction, and lymphocele

• other complications, including infection, malignancy, new onset of diabetes mellitus, liver disease, hypertension and CVD.

Management of graft loss

As the kidney loses its function, many of the physiological changes that occur mimic those seen with progressive renal diseases from other aetiologies. Therefore, these symptoms should be managed in a similar way to the non-transplant population, although it should be noted that the loss of a kidney transplant carries increased susceptibility to bruising and infection compared with pretransplant kidney failure. 28

Once the kidney is confirmed to have been lost, the graft may or may not need to be surgically removed. The decision as to whether or not the graft is removed is often made on a case-by-case basis, taking into consideration all perceived benefits and risks. The immunosuppression regimen can then be tapered and withdrawn while the patient returns to dialysis and waits for a new kidney to become available. However, in cases when people have not already formed antibodies to donor HLA, immunosuppression may be continued to allow access to a wider pool of potential donors. Success rates of a subsequent kidney transplant are equivocal. Some report that a subsequent transplant will generally be as good as the first,28 whereas others report inferior graft survival for those receiving their second38 or third39 transplant in comparison with those receiving their first transplant.

Management of graft loss will also include management of the psychological impact of the loss; owing to an increased risk for depression following the loss of a graft, it is recommended that depressive symptoms should be actively investigated and managed along conventional lines. 28

Induction therapy

• Basiliximab (BAS) (Simulect^®, Novartis Pharmaceuticals UK Ltd) or daclizumab (DAC), used as part of a CNI-based immunosuppressive regimen, are recommended as options for induction therapy in the prophylaxis of acute organ rejection in adults who are undergoing renal transplantation. The induction therapy (BAS or DAC) with the lowest acquisition cost should be used. 43

Maintenance therapy

• Tacrolimus (TAC) (Adoport^®, Sandoz; Capexion^®, Mylan; Modigraf^®, Astellas Pharma; Perixis^®, Accord Healthcare; Prograf^®, Astellas Pharma; Tacni^®, Teva; Vivadex^®, Dexcel Pharma) is an alternative to ciclosporin (CSA) when a CNI is indicated as part of an initial or a maintenance immunosuppressive regimen in renal transplantation for adults. The initial choice of TAC or CSA should be based on the relative importance of their side effect profiles for individual people. 43

• Mycophenolate mofetil (MMF) (Arzip^®, Zentiva; CellCept^®, Roche Products; Myfenax^®, Teva) is recommended for adults as an option as part of an immunosuppressive regimen only:

  • where there is proven intolerance to CNIs, particularly nephrotoxicity, leading to risk of chronic allograft dysfunction, or

  • in situations in which there is a very high risk of nephrotoxicity necessitating minimisation or avoidance of a CNI. 43

• Sirolimus (SRL) (Rapamune^®, Pfizer) is recommended for adults as an option as part of an immunosuppressive regimen only in cases of proven intolerance to CNIs (including nephrotoxicity) necessitating complete withdrawal of these treatments. 43

As a consequence of following this guidance, some medicines may be prescribed outside the terms of their UK marketing authorisation. Clinicians prescribing these drugs should ensure that people are aware of this, and that they consent to their use in such circumstances. 43

Since the publication of the current guidance in 2004,43 the marketing authorisation for DAC has been withdrawn. In addition, new technologies have received marketing authorisations for induction therapy [rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin^®, Sanofi)] and maintenance therapy [belatacept (BEL) (Nulojix^®, Bristol-Myers Squibb); a prolonged-release formulation of TAC (TAC-PR) (Advagraf^®, Astellas Pharma); and an oral suspension of immediate-release TAC]. In addition, another new technology [everolimus (EVL) (Certican^®, Novartis Pharmaceuticals UK Ltd)] has been studied as an immunosuppressant in renal transplantation. EVL received UK marketing authorisation in this therapy area in November 2014.

Induction therapy

Basiliximab is a monoclonal antibody that acts as an interleukin-2 receptor antagonist. It has a UK marketing authorisation for the prophylaxis of acute organ rejection in de novo allogeneic renal transplantation in adults. The Summary of Product Characteristics states that it is to be used concomitantly with CSA for microemulsion (ME)- and corticosteroid (CCS)-based immunosuppression in people with a panel reactive antibody (PRA) score of < 80%, or in a triple maintenance immunosuppressive regimen containing CSA for ME, CCSs and either azathioprine (AZA) or MMF. Higher PRA scores indicate higher immunological risk. BAS is administered intravenously.

Rabbit anti-human thymocyte immunoglobulin is a gamma immunoglobulin generated by immunising rabbits with human thymocytes. It has a UK marketing authorisation for the prevention of graft rejection in renal transplantation. The Summary of Product Characteristics states that it is usually used in combination with other immunosuppressive drugs and is administered intravenously.

Maintenance therapy

Tacrolimus is a CNI. It is available in a prolonged-release formulation and immediate-release formulations. All of these formulations (see Current National Institute for Health and Care Excellence guidance, above) have UK marketing authorisations for the prophylaxis of transplant rejection in adults who are undergoing kidney transplantation, and all are administered orally. Prograf^® can also be administered intravenously. The Commission on Human Medicines advises that all oral TAC medicines in the UK should be prescribed and dispensed by brand name only.

Belatacept is a soluble fusion protein that is designed to selectively inhibit CD28-mediated co-stimulation of T cells. BEL has a UK marketing authorisation for prophylaxis of graft rejection in adults who are receiving a renal transplant, in combination with CCSs and a mycophenolic acid (MPA). The Summary of Product Characteristics recommends that an interleukin-2 receptor antagonist is added to this BEL-based regimen. BEL is administered intravenously.

Mycophenolate mofetil is a prodrug of MPA that acts as an antiproliferative agent; generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy’s Laboratories, Mylan, Sandoz and Wockhardt.

Mycophenolate sodium. Mycophenolate is also available as an enteric-coated formulation: mycophenolate sodium (EC-MPS).

(Mycophenolate mofetil and MPS have UK marketing authorisations for use in combination with CSA and CCSs for the prophylaxis of acute transplant rejection in people undergoing kidney transplantation. Both drugs can be administered orally; MMF can also be administered intravenously.)

Sirolimus is a non-calcineurin-inhibiting immunosuppressant and acts as an antiproliferative agent. It has a UK marketing authorisation for the prophylaxis of organ rejection in adults – at low to moderate immunological risk – who are receiving a renal transplant. It is recommended to be used initially in combination with CSA and CCSs for 2–3 months. It may be continued as maintenance therapy with CCSs only if CSA can be progressively discontinued. It is administered orally.

Everolimus is an analogue of SRL and therefore is a non-calcineurin-inhibiting immunosuppressant which acts as an antiproliferative. EVL has recently (November 2014) received UK marketing authorisation for immunosuppressive treatment in kidney transplantation. It has been studied in clinical trials in numerous regimens containing one or more additional immunosuppressant (including CSA, TAC, anti-thymocyte immunoglobulin, mycophenolate, CCSs and BAS) and compared with various alternative immunosuppressive regimens in adults undergoing kidney transplantation. EVL is administered orally.

Renal societies (UK)

• British Renal Society www.britishrenal.org/.

• Renal Association www.renal.org/.

• UK Renal Registry www.renalreg.com/.

• Kidney Research UK www.kidneyresearchuk.org/.

• British Kidney Patient Association www.britishkidney-pa.co.uk/.

• National Kidney Federation www.kidney.org.uk/.

Renal societies (international)

• American Society of Nephrology www.asn-online.org/.

• American Association of Kidney Patients www.aakp.org/.

• National Kidney Foundation (USA) www.kidney.org/.

• Canadian Society of Nephrology www.csnscn.ca/.

• Kidney Foundation of Canada www.kidney.ca/.

• Australian and New Zealand Society of Nephrology www.nephrology.edu.au/.

• Kidney Health Australia www.kidney.org.au/.

• Kidney Society Auckland www.kidneysociety.co.nz/.

The database search results were exported to, and deduplicated using EndNote (X5) (Thomson Routers, CA, USA). Deduplication was also performed using manual checking. The search strategies and the numbers retrieved for each database are detailed in Appendix 1. After the reviewers completed the screening process, the bibliographies of included papers were scrutinised for further potentially includable studies.

Studies included in the previous adult and child HTA reviews65,67 were screened against the inclusion criteria for the Peninsula Technology Assessment Group (PenTAG) review for includable studies. Reference lists of included guidelines, systematic reviews and clinical trials were scrutinised for additional studies.

Study design

Only RCTs were included. Systematic reviews of RCTs were also included in order to ensure all relevant clinical trials were identified.

Population

Adults who were undergoing kidney transplantation only, and receiving immunosuppressive therapy, were included in this review. Multiorgan transplantation, the treatment of episodes of AR and individuals who have previously received a renal transplant and immunosuppression (i.e. individuals who were not undergoing the process of a new renal transplant) are outside the scope of this appraisal.

Interventions

Studies evaluating the use of the following immunosuppressive therapies for renal transplantation were included (further details in Chapter 1, Induction therapy and Maintenance therapy).

Induction therapy regimens containing:

• BAS

• rATG.

Maintenance therapy regimens containing:

• MMF

• MPS – EC-MPS

• immediate-release TAC

• TAC-PR

• BEL

• SRL

• EVL.

Under an exceptional directive from the Department of Health, these interventions can be assessed outside their existing marketing authorisation (to reflect their use in clinical practice) where there was compelling evidence of safety and effectiveness.

Comparators

The comparators of interest for induction therapies were regimens without monoclonal or polyclonal antibodies or one of the other interventions under consideration.

For maintenance therapies, the comparators were a CNI with or without an antiproliferative agent and/or CCSs or a regimen including one of the other interventions under consideration.

Outcomes

Outcomes sought from the studies fell into four main categories: mortality, graft-related outcomes, AEs data and HRQoL outcomes. Owing to the variability in evidence available and in order to ensure consistency with the modelling, measurements were restricted as follows:

• Mortality

• Graft-related outcomes:

  • graft survival – when graft loss is defined as return to chronic dialysis, retransplant, graft removal or death

  • GRF – (estimated) eGFR, which is an estimate of actual GFR; a number of formulae are available for eGFR, which may require age, weight, sex and serum creatinine level

  • time to, and incidence of, biopsy-proven acute rejection (BPAR)

  • severity of AR according to the Banff classification (grades I–III).

• AEs:

  • malignancy and post-transplant lymphoproliferative disorder (PTLD)

  • diabetes mellitus

  • infections

  • cytomegalovirus (CMV).

• HRQoL, including data on validated quality-of-life measures, for example the European Quality of Life-5 Dimensions (EQ-5D), the SF-36 and the Kidney Transplant Questionnaire (KTQ-25).

Overall assessment

The 86 included RCTs49,51,58,59,71–152 were of variable quality, but all appear to be flawed. However, as a result of reporting omissions, for most of the trials it was difficult to make a general assessment regarding quality. The quality appraisal should, therefore, be noted with caution. In fact, six72,73,95–98 of the 14 induction trials, 4075–85,91–94,99–122,153 of the 74 maintenance trials, and one123 of the two trials of both induction and maintenance either did not report, or lacked clarity on, at least five of the 10 items constituting the quality appraisal assessment.

Only four induction studies71–74 and six maintenance studies58,124–127,150 adequately addressed five or more of the 10 items of the quality appraisal assessment. However, even the reports of these trials omitted important information relating to quality, with six71–74,124,125 of the seven failing to clearly describe the procedure used for allocation concealment, and one58 failing to include an intention-to-treat (ITT) analysis.

Seven of the maintenance studies75,76,78,91–94 and two of the induction studies95,96 did not adequately address any of the items in the quality appraisal assessment. Further details of the quality of included studies, according to individual quality appraisal items, are described as follows.

Treatment allocation

Similarity of groups

Implementation of masking

Completeness of trials

Applicability of trials to the NHS

Induction therapies

Thirteen studies71–74,87,95–98,123,128,137,148 were identified focusing on induction therapies.

Details of study characteristics can be found in Appendix 5.

The majority of trials report outcomes up to 1 year, with the period of induction therapy generally continued for up to 14 days. No data for HRQoL were identified. It should be noted that, for some studies, the dose no longer reflects clinical practice; however, there were insufficient data for further analysis. Where a higher and lower dose was used in the RCT, the lower dose was selected for investigation.

Overall, no new evidence has been identified for BAS vs. PBO and additional data has been added to both rATG vs. no induction and BAS vs. no induction (Table 9). 96,148,158,160 All data for rATG compared with no induction has been identified by the PenTAG search.

Maintenance therapies

Seventy-five studies were identified focusing on a combination of 30 maintenance therapy comparisons (Table 10). Details of study characteristics can be found in Appendix 5.

Outcomes are reported up to a maximum of 5 years, although the majority of data available is reported at 1 year. No data for HRQoL were identified. As for induction therapy RCTs, in some cases the dose no longer reflects clinical practice; however, there were insufficient data for further analysis. When a higher and lower dose was used in the RCT, the lower dose was selected for investigation.

Other than for the TAC + AZA against CSA + AZA combination, the majority of data were identified by the PenTAG search.

Induction therapies

Baseline characteristics of trial participants for induction therapy are summarised in Table 11.

Mean age across studies ranges from 30.3 to 51.3 years. Men generally represented a higher proportion of the participants (57.5–76.3%) other than in the study reported by Mourad et al. ,98 in which men constituted 28.6% and 30.5% of the BAS and rATG arms, respectively.

Earlier papers tended to record cadaveric donors, with no further details; however, newer trials report deceased donors as DCD, DBD and ECD. Four studies71,87,128,148 used only cadaveric donors and one study97 used only living donors. In the remainder of the studies, the donors were either mixed or not reported.

The majority of studies had a high proportion of white participants: 60.3–96.2%. Brennan et al. 167 and Kahan et al. 72 report a comparatively high percentage of black participants in the BAS and rATG arms, respectively (28.5% and 29.1%; 27% and 34%, respectively).

The mismatching of HLAs ranges from 2.13 to 4 (see Chapter 1, Management of kidney transplant). Although a close antigen match is no longer considered to be critical because immunosuppressive therapy is more effective, a better HLA match may lead to longer the graft survival.

Maintenance therapies

Baseline characteristics of trial participants for maintenance therapy are summarised in Table 12.

Mean age across studies ranges from 29.6 to 57.1 years. Men represented 50–80% of participants for the bulk of the studies. The studies by Baboolal et al. 82 and Campos et al. 83 fell slightly below this, with men at 48–49%, whereas Chen et al. 121 recruited only 24% and 35% in treatment arms and Grinyo et al. 51 recruited 33% and 38%.

As for induction therapies, earlier papers tended to record cadaveric donors, with no further details. Fifteen studies75,77,80–82,88,89,99,116,129,130,134,136,138,148 used only cadaveric donors and no studies used only living. For the remainder of the studies, the donors were either mixed or not reported.

The majority of studies had a high proportion of white participants; however, Jarzembowski et al. 99 recruited all African American participants, Ciancio et al. 106 recruited Hispanic (29.3% and 30.7%) and African American (26.7% and 32.0%) participants, Chadban et al. 152 reported Asian participants to be 38.8%, 46.7% and 40.4% in each arm, Anil Kumar et al. 110 recruited 59% and 60% African American participants, and Anil Kumar et al. 122 recruited 50–54% African American participants in each arm.

For the maintenance studies, HLA is reported in a variety of formats, making any comparisons between studies difficult. As previously mentioned, the matching of HLAs is no longer considered critical, but may have an impact on graft survival.

BAS compared with PBO/no induction

The 2005 review identified four RCTs71–74 investigating the effectiveness of BAS compared with PBO. One RCT95 was identified in the review by Yao et al. 67

No additional studies were identified in the PenTAG search. No data were identified for HRQoL and time to BPAR.

For BAS compared with no induction, one RCT97 was identified in TA99 and two further RCTs123,128 were identified by the PenTAG search.

Mortality

Participant mortality was recorded at 6 months by three studies. 73,74,123 Six studies71–74,97,128 report mortality at 1 year.

As displayed in Table 13 and Figure 8, the OR at 0.5 years for the studies by Ponticelli et al. ,73 Albano et al. 123 and Lawen et al. 74 indicates that BAS is associated with lower odds of mortality, although the results are not statistically significant (OR 0.36, 95% CI 0.13 to 1.01).

TABLE 13 - Mortality for BAS vs. PBO/no induction

NA, not applicable.

One trial excluded from pooled analysis as a result of no deaths in either arm.

Two trials excluded from pooled analysis as a result of no deaths in either arm.

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Albano 2013,123 Ponticelli 2001,73 Lawen 200374	0.5	3a	0.36	0.13 to 1.01	0.0	0
Kyllönen 2007,128 Kahan 1999,72 Nashan 1997,71 Ponticelli 2001,73 Lawen 2003,74 Sheashaa 200397	1	6b	0.95	0.49 to 1.87	0.0	0
Sheashaa 200397	3	1	0.33	0.01 to 8.21	NA
	5		0.19	0.01 to 4.10
	7		1.00	0.24 to 4.24
	10		0.78	0.20 to 3.10

FIGURE 8.

Forest plot: mortality for BAS vs. PBO/no induction.

Pooled results at 1 year for the studies by Lawen et al. 74 and Sheashaa et al. 97 also display no statistically significant difference between BAS and PBO/no induction up to 1 year, which is in agreement with the previous HTA65 (OR 0.95, 95% CI 0.49 to 1.87). The effect estimate for the Sheashaa et al. 97 study at 3, 5, 7 and 10 years also shows no difference between arms.

Graft loss

Of the seven studies in this group,71–74,97,123,128 three studies73,74,123 recorded graft loss at 6 months and six studies71–74,97,128 at 1 year (Table 14 and Figure 9).

TABLE 14 - Graft loss for BAS vs. PBO

NA, not applicable.

One trial excluded owing to no graft loss in either arm.

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Albano 2013,123 Ponticelli 2001,73 Lawen 200374	0.5	3	0.78	0.50 to 1.22	0.0	0.0
Kyllönen 2007,128 Kahan 1999,72 Nashan 1997,71 Ponticelli 2001,73 Lawen 2003,74 Sheashaa 200397	1	6a	0.82	0.56 to 1.21	0.0	0.0
Sheashaa 200397	3	1	3.06	0.12 to 76.95	NA
	5		5.21	0.24 to 111.24
	7		1.00	0.24 to 4.24
	10		0.78	0.20 to 3.10

FIGURE 9.

Forest plot: graft loss for BAS vs. PBO/no induction.

At both time points the OR may indicate some benefit of BAS compared with PBO or no induction in reducing graft loss (0.5 years: OR 0.78, 95% CI 0.50 to 1.22; 1 year: OR 0.82, 95% CI 0.56 to 1.21). However, this estimate must be treated with caution because of the wide CIs indicating a lack of statistical significance.

The one study97 reporting results at 3, 5, 7 and 10 years showed no statistically significant difference between arms (see Table 14).

Graft function

Pooled analysis for GRF measured as CRC (Table 15 and Figure 10) implies no beneficial effect of BAS compared with PBO [0.5 years: weighted mean difference (WMD) –1.38 ml/minute/1.73 m², 95% CI –5.96 to 3.20 ml/minute/1.73 m²; 1 year: WMD 1.93 ml/minute/1.73 m², 95% CI –0.97 to 4.83 ml/minute/1.73 m²]. 71–73,97,123 In particular, results for 0.5 years must be treated with caution because of the substantial heterogeneity across studies (I² = 83.4%). It should also be noted that, at 1 year, the study reported by Kahan et al. ,72 which indicates an improved GRF for participants on BAS, had a higher percentage of African American participants (34% and 27%) who generally exhibit poor long-term graft survival compared with other ethnic groups. 72

TABLE 15 - Pooled analysis for BAS vs. PBO/no induction: GRF

WMD, weighted mean difference.

Study	Time point (years)	Trials	WMD (ml/minute/1.73 m2)	95% CI (ml/minute/1.73 m2)	I2 (%)	τ2
Albano 2013,123 Ponticelli 2001,73 Nashan 199771	0.5	3	–1.38	–5.96 to 3.20	83.4	0.06
Kyllönen 2007,128 Kahan 1999,72 Nashan 1997,71 Ponticelli 2001,73 Lawen 2003,74 Sheashaa 200397	1	4	1.93	–0.97 to 4.83	23.9	5.75

FIGURE 10.

Forest plot: GRF for BAS vs. PBO/no induction. SD, standard deviation; WMD, weighted mean difference.

Data up to 10 years reported by Sheashaa et al. 97 (Table 16) indicate no statistically significant difference between BAS and no induction.

TABLE 16 - Graft function for BAS vs. no induction (unpooled)

SD, standard deviation.

Note

All methods either reported as CRC or Cockcroft–Gault unless otherwise stated.

Study	Time point (years)	BAS, mean ml/minute/1.73 m2 (SD)	No induction, mean ml/minute/1.73 m2 (SD)	MD (ml/minute/1.73 m2)	95% CI (ml/minute/1.73 m2)	p-value (t-test)
Sheashaa 200397	1	75.0 (14.1)	72.0 (12.9)	3.00	–2.30 to 8.30	0.2697
	3	76.6 (12.9)	72.3 (13.7)	4.34	–0.88 to 9.56	0.1094
	5	73.4 (16.2)	71.3 (12.3)	2.19	–3.44 to 7.82	0.4671
	7	71.2 (14.5)	68.6 (14.4)	2.60	–3.06 to 8.26	0.3705
	10	64.1 (15.2)	65.5 (15.1)	–1.40	–7.15 to 4.35	0.6451

Biopsy-proven acute rejection

The results of BPAR at 0.5 years are inconclusive because of the substantial heterogeneity across studies (I² = 80.7%). 71,73,74,123 In contrast, at 1 year, BAS statistically significantly reduced BPAR compared with PBO/no induction (OR 0.53, 95% CI 0.40 to 0.70, I² = 0.0%) (Table 17 and Figure 11). 72–74,97,128 Furthermore, the report by Sheashaa et al. 97 indicates this effect is maintained up to 10 years (OR 0.41, 95% CI 0.18 to 0.96). 97

TABLE 17 - Pooled analysis for BAS vs. PBO: BPAR

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Albano 2013,123 Ponticelli 2001,73 Lawen 2003,74 Nashan 199771	0.5	4	0.59	0.31 to 1.10	80.7	0.064
Kyllönen 2007,128 Kahan 1999,72 Ponticelli 2001,73 Lawen 2003,74 Sheashaa 200397	1	5	0.53	0.40 to 0.70	0.0	0.0

FIGURE 11.

Forest plot: BPAR for BAS vs. PBO.

rATG vs. no induction

Both RCTs for this comparison were identified via the PenTAG search. 96,148

BAS vs. rATG

The RCT reported by Lebranchu et al. 87 was identified in the 2005 review. The PenTAG search retrieved a further two RCTs: Brennan et al. 137 and Mourad et al. 98 All three RCTs87,98,137 had a maintenance therapy comprising CSA, MMF and CCSs.

Mortality

The comparison between BAS and rATG for mortality is reported by three studies87,98,137 (Table 25 and Figure 12). Two studies are pooled with 1-year results where no statistically significant effect is seen between arms (OR 1.03, 95% CI 0.35 to 3.00). 98,137

TABLE 25 - Mortality for BAS vs. rATG

NA, not applicable.

Note

One trial excluded from pooled analysis as a result of no deaths in either arm.

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Lebranchu 200287	0.5	1	3.06	0.12 to 76.95	NA	NA
Mourad 2004,98 Brennan 2006137	1	2	1.03	0.35 to 3.00	0.0	0.0

FIGURE 12.

Forest plot: mortality for BAS vs. rATG.

Graft loss

Data from three trials87,98,137 were pooled at the 1-year time point (Table 26 and Figure 13). Although the OR indicates lower odds of graft loss associated with rATG, the effect is not statistically significant (OR 1.36, 95% CI 0.61 to 3.03). There was no evidence of heterogeneity across studies. For the individual study87 at 0.5 years there was no statistically significant effect for BAS or rATG.

TABLE 26 - Graft loss for BAS vs. rATG

NA, not applicable.

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Lebranchu 200287	0.5	1	1.00	0.14 to 7.39	NA	NA
Lebranchu 2002,87 Mourad 2004,98 Brennan 2006137	1	3	1.36	0.61 to 3.03	0.0	0.0

FIGURE 13.

Forest plot: graft loss for BAS vs. rATG.

Biopsy-proven acute rejection

A total of three studies87,98,137 report on BPAR for BAS vs. rATG (Table 28 and Figure 14). At both 0.5 years and 1 year, the 95% CIs imply a lack of statistically significant difference between treatments (0.5 years, OR 1.00, 95% CI 0.24 to 4.24; 1 year, OR 1.57, 95% CI 0.95 to 2.61). For Brennan et al. ,137 as a much larger study with narrower CIs, rATG appears to reduce BPAR, although this effect is lost when pooled with the smaller studies.

TABLE 28 - Biopsy-proven acute rejection for BAS vs. rATG

Study	Time point (years)	Trials	OR	95% CI	I2 (%)	τ2
Lebranchu 200287	0.5	1	1.00	0.24 to 4.24	0.0	0.0
Lebranchu 2002,87 Mourad 2004,98 Brennan 2006137	1	3	1.57	0.95 to 2.61	0.0	0.0

FIGURE 14.

Forest plot: BPAR for BAS vs. rATG.

TAC + AZA vs. CSA + AZA

Fourteen studies75,76,79–85,88,99,100,104,148 were identified using this combination. Where possible, meta-analysis has been performed. Results are presented for all outcomes, other than HRQoL where no evidence was reported.