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June 2023, Volume 73, Issue 6

Narrative Review

Problem to solution; from mammalian skin grafts to renal allograft rejection: a tale of 66 years of evolution of our understanding

Murtaza Dhrolia  ( Department of Nephrology, The Kidney Centre Postgraduate Training Institute, Karachi, Pakistan. )
Aasim Ahmad  ( Department of Nephrology, The Kidney Centre Postgraduate Training Institute, Karachi, Pakistan. )

Abstract

The first successful kidney transplant was done in 1954, and it remains the best option for those with failed kidneys. However, the recipient’s immune system remains the most formidable barrier to transplantation, leading to rejection. Rejection continues to be the most important reason of graft malfunction and chronic renal allograft dysfunction and remains a challenge to date for successful transplant survival. The current narrative review was planned to find the best possible solution to the problem from among the different solutions presented in literature related to allograft rejection since 1954.

 

Keywords: Evolution, Renal transplantation, Allograft rejection, Immunosuppressant.

 

DOI: 10.47391/JPMA.6600

 

Submission completion date: 08-04-2022

 

Acceptance date: 19-11-2022

 

Introduction

To achieve the best solution to renal allograft rejection, the current narrative review adopted the system of classifying and grabbing the problem, finding alternatives, and picking the finest solution, registering directions to resolve the problem, and to evaluate the solution based on the evolution of our understanding of renal allograft rejection since 1954 when the first successful kidney transplant was done.

 

Step 1: Classifying the problem

Diagnosing renal allograft rejection; Evolution of Banff classification:

 

Until the 1990s, few individual classifications with heterogeneous characterisation for renal allograft rejection had been developed.1 In 1991, all those associated with transplants, like pathologists, nephrologists and transplant surgeons, gathered in Banff, Canada, and developed a schema to standardise the international classification of renal transplanted (RT) biopsies, which was finally published in March 1993.2

Thereafter, Banff Classification has been updated bi-annually in the light of latest evidence. After the initial meeting in 1991, there have been 15 meetings targeting expansion of understanding in the field of renal transplantation. The last meeting was held in 2019 in Pittsburgh, Pennsylvania, in the United States of America (USA).3

 

Step 2: Understanding the problem

Evolution of understanding related to the mechanism of renal allotransplant rejection:

The acquired immune system comprises two response mechanisms, cytotoxic T-cells and antibodies. Sir Peter Medawar, in 1943 and 1944, did revolutionary work in transplant immunology by showing that a second skin graft was rejected more quickly and easily because of active immunisation from the initial graft.4,5

Billingham and Medawar6 observed that the skin allografts given to rodents that did not have T-cells were not rejected, and giving them the T-cells reinstated the rejection. This led to the notion that T-cells were the only reason for the allotransplant rejection. Formation of antibodies after transplantation was initially reported in 1938.7 In the early 1970s, the occurrence of already formed donor-specific antibodies (DSAs) established as a high-level risk for hyperacute rejection8 and the development of DSAs post-transplantation caused poorer outcomes and showed lesions of vascular obliteration now called allograft vasculopathy.9

 

Our current understanding: Based on observations and continued research in the field of transplant immunology,10-23 the understanding about the mechanism of rejection is that alloimmune responses are initiated in well-defined stages10 and T- and B-cells are the chief modes of the adaptive immune response, as they not only contribute a significant part to the acute phase, but also have a part in the healing phases of ischaemia-reperfusion injury (IRI).11

Antigen-inexperienced or naïve T-cells of the recipient in secondary lymphoid organs are activated through the innate immune-recognition system by antigen-presenting cells (APCs), chiefly the dendritic cells (DCs) of the donor.12-14 Activation of B-cells occur when antigen attaches its receptors, and thus produce anti-donor human leukocyte antigen (HLA) alloantibodies.16

The activation of the T-cell requires three events. Signal-1-Presentation of donor antigen to DCs through the T-cell receptor (TCR) is transduced through the cluster of differentiation-3 (CD3) complex.17,18 Signal-2-DCs cause additional stimulation, which occurs when DCs B7.1 (CD80) and B7.2 (to T-cells CD28.19  Signal 3 is activated by Signals 1 and 2 and it initiates cell proliferation via three CD86) attach pathways: the calcium-calcineurin,  the nuclear factor –ҡBand mitogen-activated protein kinase (MAPK) pathways.20 These pathways activate interleukin-2 (IL2), CD154 and CD25 which then activate the mammalian target of rapamycin (mTOR) pathway.21 This leads to a formation of effector T-cells which along with alloantibodies mediate allograft rejection.

 

Step 3: Identifying alternative solutions

Evolution of immunosuppressive agents for renal allograft rejection:

Over the last six decades, major advances in immune suppression to prevent rejection have been achieved. It began with total lymphoid irradiation to what is now available which has dramatically decreased episodes of acute rejection and significantly increased graft survival in the short term. Nevertheless, long-term graft outcome is still a substantial problem caused by antibody-mediated rejection and chronic allograft dysfunction.

 

Total lymphoid irradiation: Successful skin homograft with high dosage X-radiation and homologous bone marrow was recommended in 1955 by Joan Main et al.24, and in 1958 by Joseph Murray et al.25 to use total lymphoid irradiation (TLI) as the initial approach of immunosuppression. Later, , from 1960 to 1962, four success stories were reported which started with total body irradiation.26,27 As bone marrow inoculation was not done, chimerism may not be essential. As newer alternatives became available,28 TLI went obsolete.

 

Corticosteroids: Early in 1930, human adrenal insufficiency was treated with extracts from animal adrenal cortices29 and was first used clinically in 1949 by Hench et al. for rheumatoid arthritis (RA).30 Goodwin et al. in early 196031 showed that corticosteroids could undo acute rejection in a live related RT. Starzl et al.32 in 1963 confirmed the effectiveness of corticosteroids and they became conventional therapy for renal transplantation.

 

Azathioprine (AZA): Schwartz et al. initiated immunosuppression by pharmacological means in 1959 by showing that the antiproliferative drug, 6-mercaptopurine (6-MP) reduced the formation of antibodies, thereby extending rabbit skin allograft survival.33 Sir Roy Calne et al. in 1960 for the first time used the imidazole derivative of 6-MP, AZA, and showed that  renal graft survival in dogs could be significantly improved from 7.5 to 23.7 days.34 Till 1978, AZA and high-dose prednisolone remained the conventional therapy for RT.35

 

Calcineurin inhibitors (CNIs): In 1969, cyclosporine (CsA) was derived from tolypocladiuminflatuma fungus in the soila and showed an immunosuppressive effect in transplantation by Jean F. Borel.36 Successful trials were done in 197837,38 and protocols with CsA regimen for immune suppression were used worldwide in 1982.39

In 1987 tacrolimus developed from streptomyces tsukubaensis (soil fungus) was observed to be more potent than CsA40. Non-adherence, a major cause of renal allograft rejection,41 is addressed by prolonged-release tacrolimus approved in several countries since 2007.42

 

Mycophenolate mofetil (MMF): Following promising preclinical and phase-I clinical trials43, MMF, an anti-metabolite, was considered an effective and safe immunosuppressant44 and in 1995 it replaced AZA as the immunosuppressive agent of choice in kidney transplantation.45

 

mTOR inhibitors: In1989, it was shown that rapamycin (RPM), an mTOR inhibitor and a secondary metabolite of streptomyces hygroscopicus, reduced rejection in solid organ transplants in experimental animals46,47, but the mTOR inhibitor was first used in human RT in 1999.48 The introduction of mTOR inhibitors sirolimus and everolimus allowed early and significant CNI reduction/withdrawal without compromising safety or efficacy in the early post-transplant period.49

 

Antibodies: In the mid-1960s came polyclonal antibodies, like antilymphocyte aerum (ALS), antilymphocyte globulin (ALG) and rabbit antithymocyte globulin (rATG). From the 1970s, these were used to defer the start of acute rejection.50 Polyclonal antibody use has a higher risk of infection and malignancy, and, with the development of CsA, their use was reduced drastically. ATG is now being used again with confidence as better prophylaxis for viral infections as our understanding of viral aetiology of post-transplant lymphoproliferative disorder (PTLD) has become better.51

Monoclonal antibodies (mAbs) were developed in 1975 and had monoclonal specificity unlike the polyclonal preparations.52

In the early 1980s, Anti-CD3 mAb muromonab (OKT3) was the first mAb used in sensitised patients for induction, for the treatment of rejections that were steroid-resistant, and in patients whose transplant function was delayed. This helped postpone CNI initiation.53 It is no longer in use because of its serious side-effects and the availability of new agents with less side effects.

In the late 1990s, several mAbs were developed, and anti-CD25 antibodies that block interleukin-2 (IL-2) receptors, daclizumab and basiliximab, came into clinical use as they decreased the frequency of acute cellular rejection.54,55

Alemtuzumab: An anti-CD52, T-cell and B-cell-depleting mAb, initially used for induction in renal transplantation in the late 1990s56, was used in the early 20th century with excellent results,57,58 but some studies showed that alemtuzumab may have increased rates of acute or antibody-mediated rejection.59,60

In 1997, rituximab, an anti CD20 mAb, was first approved for the treatment of B-cell non-Hodgkin's lymphoma.61 Rituximab was first used for treating resistantRT rejection in 200062. Rituximab is effectively used for many antibody-mediated events, including desensitisation in transplants that have incompatibility with blood group ABO, transplant with a positive crossmatch after removal of antibodies, and in treating antibody-mediated rejection (AMR).63,64 Where renal function has been preserved, rituximab is also used in combination with chemotherapy in the treatment of PTLD.65

 

Co-stimulatory blocker: Since 2011, fusion protein balatacept, blocker of co-stimulatory signals, has been in use as a biological non-nephrotoxic maintenance immunosuppressant.66

Co-stimulatory blockers, bleselumab (ASKP1240),67 a fully humanised anti-CD40 mAb, and CFZ533,68 a fully humanised, anti-CD40 mAb, are under investigation in clinical trials for preventing rejection without the use of CNIs along with their inherent nephrotoxicity.

Blocking co-stimulatory signals at multiple levels is found to be useful in transplantation. Molecules that target other co-stimulation sites, like anti-CD28 antibodies, FR104, a non-agonistic, pegylated monovalent humanized Fab antibody,66 will likely be developed. Use of two co-stimulatory blockers, e.g. against CD40-CD154 and against CD28-CD80 pathway, were found to be effective in animal research and may be used in humans in the future.66

 

Bortezomib: Bortezomib is a proteasome inhibitor that depletes plasma cells and thereby inhibits antibody production. It was first synthesised in 1995, and was approved in 2002 by the Food and Drug Administration (FDA) as a treatment for multiple myeloma.69 It is also used for pre-transplant desensitisation and treatment of AMR. Since 2005, it is also being used off-label to decrease DSAs in patients who are highly sensitised was described in 2008 as an additional treatment for AMR.70,71

 

Eculizumab: Eculizumab is a monoclonal immunoglobulin G (IgG) antibody against protein C5 that can diminish the propagation of complement cascade after antibody-antigen binding. It was approved for the treatment of paroxysmal nocturnal haemoglobinuria (PNH)72 in 2007, and for atypical haemolytic uraemic syndrome (aHUS) in 2011. It was evaluated in several clinical trials in transplant patients to reduce the end results of IRI, to prevent, treat relapsing or de novo aHUS, and in high immunological risk to prevent and cure humoral rejection.73-75

 

Protein C1 inhibitor: Protein C1 inhibitor (C1-INH) inhibits complement activation, both classical and lectin pathways, and prevent leukocyte-endothelial cell adhesion76.  C1-INH is used safely with some success in hereditary angioedema77.  C1-INH is currently under evaluation in renal transplantation to see a reduction in IRI and delayed graft function. It is also being evaluated for its potential to decrease sensitisation and reduction in donor-specific antibody production. This is likely to help in AMR, and conditions that may be refractory to other treatments.78,79

Sutimlimab, a humanised mAb against complement factor C1s that inhibits the classical complement pathway is also under investigation.80,81

 

Tocilizumab: Tocilizumab, an IL-6 receptor antagonist, is being tested for chronic active AMR with positive DSAs and transplant glomerulopathy which is unaffected by intravenous immunoglobin (IVIG) and rituximab with and without plasmaperesis (PP).82,83

 

Cell-based therapy for immune tolerance induction: Cell-based treatments helps chimerism and causes tolerance in major histocompatibility in different recipients. These are recently under evaluation in several trials to replace or at least spare conventional immunosuppressive therapies.84-87 Recently, a case was reported of a living kidney transplant that achieved immune tolerance by mesenchymal stromal cells (MSC) derived from bone marrow.88

 

Use of IgG-degrading enzyme from Streptococcus pyogenes (IdeS): IdeS, derived from streptococcus (S.) pyogenes, inhibits both complement-dependent and antibody-dependent cellular cytotoxicity by cutting human IgG into fragments and preventing IgG memory B-cell responses by slicing the B-cell receptor from the circulating B-cells, thereby reducing, or eliminating DSAs and helping in desensitisation.89

 

Step 4: Selecting the best solution

Evolution of major clinical trials evaluating the effectiveness of immunosuppressive agents for renal allograft rejection:

A delicate balance must be achieved between over-immunosuppression and under-immunosuppression. The former increases the risk of infection, and the latter increases the risk of rejection. A discussion of some of the clinical trials may lead to the selection of the best possible solution to combat the problem of allograft rejection.

 

TLI vs CsA: A prospective randomised trial, consisting of 20 kidney transplant patients who developed end-stage renal disease (ESRD) secondary to diabetic nephropathy, compared TLI given before the surgery with CsA therapy given after the surgery. Significantly more frequent rejection episodes occurred in the TLI-treated recipients, but the 3-year patient and transplant survival and infectious complications were comparable in both groups.90

Result: TLI has fallen out of favour.

 

Low-dose vs. high-dose steroids vs complete avoidance of steroids: It was found that low-dose (3mg/kg IV bolus) steroids given IV was as effective as high-dose (15-30 mg/kg IV bolus) steroid in reversing acute rejection, and it did not increase the incidence of further rejection episodes.91

A randomised trial in which rATG or Interleukin-2 receptor alpha (IL-2RA) was used for induction and maintenance regimen was tacrolimus/CsAe and MMF found that early removal of steroids did not raise the rate of acute rejection or graft failure.92,93

Result: Lower dose or steroid-sparing strategies are now being considered inRT because of the availability of potent maintenance and induction agents.

 

AZA vs. MMF: Three major studies showed substantial reduction in acute rejection episodes with MMF compared to AZA at six months. However, graft and patient survivals were similar at one year.94-96

Comparison of MMF with azathioprine in about 50,000 kidney transplants in the United States renal database system showed that MMF had a protective effect on deteriorating graft function at one year.97

Result: MMF has replaced AZA in most immunosuppressive protocols.

 

CsA-steroid vs. AZA-steroid: The survival rate of cadaveric RTs at one year, treated with CsA and steroids were better compared to recipients treated with Az=ZA and steroids in a 1981 study of 96 patients.98

Result: CsA became the cornerstone of immunosuppression regimens all over the world.

 

CsA vs. tacrolimus: A study showed that individuals on CsA had more hyperuricaemia, and higher systolic and diastolic blood pressure at one year compared to tacrolimus and sirolimus.99

A meta-analysis of 30 trials which compared tacrolimus and CsA revealed substantial decrease in graft loss, lower acute rejections and less steroid-resistant rejection in tacrolimus-treated recipients, but it showed a higher incidence of diabetes needing insulin, tremor, headache and gastro-intestinal (GI) symptoms, like nausea, vomiting and diarrhoea. Those treated with CsA had more constipation and hirsutism. There were no disparities in the infection or malignancy rates.100

A 5-year study done on 169 patients in Pittsburgh in which patients were shifted to tacrolimus from CsA because of intractable rejection showed 74% success rate in combating rejection with steroid withdrawal in 22% cases.101

In a large European study, CsA-induced toxicities, like gingival hyperplasia, hypertrichosis, hyperlipidaemia and hypertension, became better after conversion to tacrolimus.102

Result: Tacrolimus progressively replaced CsA because of better results and fewer side effects.

 

Tacrolimus-MMF vs. Tacrolimus-AZA vs. CsA-MMF: In a trail that compared tacrolimus-AZA, CsA-MM, and tacrolimus-MMF found that the rate of acute rejection was not different between these groups, but they differed in the need for ATG (4.2% in tacrolimus-MMF arm, 10.7% in the CsA-MMF group, and 11.8% in the tacrolimus-AZA group). Patient and graft survival at 1, 2 or 3 years were, however, similar.103

A meta-analysis of 9 randomised controlled trials (RCTs) with 1820 participants looked at the effect of steroid withdrawal at 3-6 months of RT showed higher rates of acute rejection with CsA-MMF compared to tacrolimus-MMF.104

Result: Maintenance regimen for kidney transplant recipients comprised mainly tacrolimus-MMF.105

Importance of CNIs in regimen: Studies used MMF-steroids with sirolimus,106 basiliximab with sirolimus,107 or belatacept with basiliximab without CNIs, but showed higher acute rejection rates.108

A Spanish study showed that out of patients treated with MMF, although 65% remained CNI-free at 12 months, the number came down to only 36% at 5years.109

 

Sirolimus-Everolimus vs CNIs: Combining sirolimus with MMF showed reduction in acute rejection, more delayed graft function and reduction in graft survival in RT recipients compared to a combination of tacrolimus-MMF or CsA-MMF regimens.110 However, studies two large radomised trials99,111 showed that combining sirolimus and MMF had inferior results than a combination of low-dose tacrolimus-MMF-based triple therapy.

Webster et al.112 revealed that when sirolimus or everolimus replaced CNI, episodes of acute rejection remained comparable, with a lower serum creatinine, but bone marrow was more suppressed.

Many trials examined the impact of everolimus on withdrawal of CNI in RT recipients. Studies of an early switch to everolimus or halving of CNI dose followed by complete withdrawal at 2 months resulted in high percentage of biopsy-proven acute rejection (BPAR) at 1 year113,114. Studies of late conversion (mean >5-7 years) did not show increased numbers of acute rejection.115,116

Result: CNI remains the mainstay of maintenance regimen. Limited use of mTORs can be beneficial in patients with deteriorating kidney function using CNIs, and in those with malignant neoplasms, or non-melanoma skin cancers.

Everolimus-CNIs vs. MMF-CNIs: Maintenance therapy with tacrolimus-MMF appears to be better than either tacrolimus-sirolimus or CsA-sirolimus.117

Studies and trials118-121 looked at the efficacy of everolimus with reduced CNI and compared it with conventional MMF, and standard CNI. Everolimus helped in decreasing CNI dose, thereby reducing the risk of nephrotoxicity with mild-to-moderate immunologic risk. Everolimus was non-inferior to MMF for its immunosuppressive effectiveness and preservation of graft function.

Result: Reduced doses of CNIs combined with everolimus may have better graft survival and stable renal function.

 

Belatacept vs CsA: In two trials122,123 the group that received belatacept showed similar percentage of graft and patient survival along with better renal function over a 7-yr post-transplant follow-up124 and less frequent de novo DSA development with better cardiovascular and metabolic risk profiles125 compared to the CsA group. However, at 12 months post-transplant, treatment with belatacept showed increase in acute cellular rejection, and PTLD, particularly in seronegative Epstein Barr virus-negative patients.122,123

Result: Caution is required for the use of belatacept as part of immunosuppressive regimens.

 

rATG vs. IL-2RA antagonists: A meta-analysis looked at the role of IL-2RA compared to rATG on the rate of acute rejection, infections, graft and patient survival in RT patients getting tacrolimus with no major difference in the rate of acute rejection or patient and graft survival between the groups, but cytomegalovirus (CMV) infection were less in IL-2RA group. In subgroup analysis in high-risk transplants, acute rejections were more in then IL-2RA group than in the rATG group.126

Brennan et al.127 compared rATG and IL-2RA in 278 patients who had increased probability of delayed transplant function and/or acute rejection. It showed rejection incidence to be almost half in the rATG arm at 1 and 5 years along with decreased severity. All patients received maintenance with cyclosporin, MMF and prednisolone.

In a meta-analysis of 6 studies with a total of 853 patients, Liu et al. compared rATG and basiliximab, showing lower infection risk in the basiliximab group, but the rate of acute rejection, delayed transplant function, and the loss of the transplanted kidney of the patient were not different.128

Brokhof et al. assessed the effect of rATG and basiliximab on DSA in 114 cadaveric kidney recipients with positive DSA but negative flow crossmatch, and followed up for 36 months. The ATG group had much lower level of DSAs and decreased incidence of AMR.129

Result: ATG is preferable in patients at high risk of rejection.

 

Ritaximab in acute AMR(AAMR) and chronic AMR (CAMR): A trial130-131 recruited 38 patients with AMR within one year of kidney transplant and compared the effect of rituximab or placebo infusion, given on the 5th day of the transplant. All patients received comparable anti-human leukocyte antigens (HLA) sensitisation with plasma exchanges, IVIG and steroids. Both groups showed similar one-year transplant survival and kidney function,130 and there was no difference at 7 year on death-censored transplanted kidney’s survival and its function. Infection rates were also similar, but there were seven cancers in the rituximab group.131

A systematic review of seven studies evaluated the application of rituximab in CAMR treatment. Only one study showed improved graft outcomes; three reported poorer outcomes and three showed no difference. In one study, rituximab was associated with an increase in adverse events.132

Result: Rituximab may have some benefit in AAMR though high-quality evidence is lacking. Rituximab does not appear to have any benefit in CAMR.

 

Bortezomib in late AMR: A trial133 revealed that bortezomib and placebo groups were comparable when compared for glomerular filtration rate (GFR) (median measured) at 2-years, 24-month graft survival, DSA levels, urinary protein concentration or follow-up biopsy samplings, while the bortezomib group showed more GI and haematological side effects.

Result: Treatment with bortezomib for late AMR is still unsettled.

 

Step 5: List of instruction to solve the problem

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline related to kidney transplant recipients (KTRs):

Only KDIGO clinical practice guidelines134 on the monitoring, management and treatment of KTRs dating back to 2009 based upon the best information available as of March 2009 is the on guideline available for transplant-care providers (Table).

 

 

Step 6: Evaluating the solution

Key challenges and the possible ways forward in renal allograft rejection:

Acute rejection has decreased, but the long-term outcome of kidney transplantation has not much changed. The main reason for graft-loss remains chronic rejection. Infections, diabetes, drug-related toxicity, and chronic kidney disease (CKD) still occur, mainly due to the immunosuppression therapy. Therefore, strategies are needed to safely minimise immunosuppression, thereby reducing long-term poor outcomes and cost of kidney transplantation.

Several important studies with some new recommendations have been done after the publishing of the 2009 KDIGO guideline for KTRs. New guidelines are needed to help nephrologists in deciding if induction is needed, which medications to use for induction, and what is the ideal maintenance treatment.

In the era of tacrolimus, mycophenolic acid and steroids, questions are raised about the requirement for IL-2RA in kidney transplantation,135 as it is not useful in standard-risk transplantation, and in high-risk transplants it may be inferior to rATG.127

In search of regimen with CNI avoidance, belatacept promises a better long-term kidney function, graft function and a better patient survival rate,124 but because of its prohibitively high cost, routine use is not possible. Based on studies on everolimus118-121, minimal doses of CsA with everolimus are non-inferior for graft survival and stable renal function to MMF, and may replace MMF in conventional regimen suggested by KDIGO 2009.134

The newer innovations to improve renal transplant outcomes are likely to come from defining biomarkers of allo-reactivity and strategies to improve clinical tolerance. Personalised immunosuppression may offer the best treatment to individual patient after transplantation. In the field of clinical tolerance, much work is needed before it can replace conventional transplant therapy.

Xenotransplantation is not merely a dream as in 2016, the International Society for Organ Donation and Procurement (ISODP) Congress in Seoul predicted that th world might see a xenotransplant by 2030. Genetically modified pigs are already a reality136, and on October 19, 2021, for the first time, a human was transplanted with a kidney from a pig without an immediate immune rejection for 54-hours.137 However, concerns related to thrombogenicity and transmission of unknown infections would remain even if the problems of immunotolerance and immunosuppression are solved.

Similarly, using patient’s own cells that are cultured naturally, or printed by a three-dimensional (3D) printer, is already being done and some models (urine bladder) are in clinical trials for more than 10 years, with very promising results.138

Unfortunately, the future with xenotransplantation and personalized medicine is still far away, and many challenges still abound in transplantation today that needs to be resolved.

 

Disclaimer: None.

 

Conflict of Interest: None.

 

Source of Funding: None.

 

References

 

1.      Solez K, Racusen LC. The Banff classification revisited. Kidney Int 2013; 83: 201-6.

2.      Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993; 44: 411-22.

3.      Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al.  The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell–and antibody‐mediated rejection. Am J Transplant 2020; 20: 2318–31.

4.      Medawar PB. The behaviour and fate of skin autografts and skin homografts in rabbits: A report to the War Wounds Committee of the Medical Research Council. J Anat 1944; 78: 176-99.

5.      Medawar PB. A second study of the behaviour and fate of skin homografts in rabbits: A Report to the War Wounds Committee of the Medical Research Council. J Anat 1945; 79(Pt 4): 157-76.

6.      Billingham R, Medawar PB. The technique of free skin grafting in mammals. J Exp Biol 1951; 28: 385-402.

7.      Gorer PA. The antigenic basis of tumour transplantation. J Pathol Bacteriol 1938; 47: 231-52.

8.      Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 1969; 280: 735-9.

9.      Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS. Humoral antibodies in renal allotransplantation in man. N Engl J Med 1970; 282: 111-7.

10.    Heeger PS, Dinavahi R. Transplant immunology for non-immunologist. Mt Sinai J Med 2012; 79: 376-87.

11.    Huang Y, Rabb H, Womer KL. Ischemia–reperfusion and immediate T cell responses. Cell Immunol 2007; 248: 4-11.

12.    Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic ‘ignorance’of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 2000; 6: 686-8.

13.    Chalasani G, Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci 2002; 99: 6175-80.

14.    Thaunat O, Graff-Dubois S, Brouard S, Gautreau C, Varthaman A, Fabien N, et al. Immune responses elicited in tertiary lymphoid tissues display distinctive features. PloS one 2010; 5: e11398.

15.    Valujskikh A, Lakkis FG. In remembrance of things past: memory T cells and transplant rejection. Immunol Rev 2003; 196: 65-74.

16.    Pape KA, Kouskoff V, Nemazee D, Tang HL, Cyster JG, Tze LE, et al. Visualization of the genesis and fate of isotype-switched B cells during a primary immune response. J Exp Med 2003; 197: 1677-87.

17.    Reiser JB, Darnault C, Guimezanes A, Grégoire C, Mosser T, Schmitt-Verhulst AM, et al. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat Immunol 2000; 1: 291-7.

18.    Wange RL, Samelson LE. Complex complexes: signaling at the TCR. Immunity 1996; 5: 197-205.

19.    Li XC, Rothstein DM, Sayegh MH. Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 2009; 229: 271-93.

20.    Wang D, Matsumoto R, You Y, Che T, Lin XY, Gaffen SL, et al. CD3/CD28 costimulation-induced NF-κB activation is mediated by recruitment of protein kinase C-θ, Bcl10, and IκB kinase β to the immunological synapse through CARMA1. Mol Cell Biol 2004; 24: 164-71.

21.    Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 2010; 22: 333-40.

22.    Sellarés J, De Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody‐mediated rejection and non-adherence. Am J Transplant 2012; 12: 388-99.

23.    Loupy A, Jordan SC. Donor-specific HLA antibodies and renal allograft failure.  Nat Rev Nephrol 2013; 9: 130-1.

24.    Main JM, Prehn RT. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst 1955; 15: 1023-9.

25.    Murray JE, Merrill JP, Dammin GJ, Dealy Jr JB, Alexandre GW, Harrison JH. Kidney transplantation in modified recipients. Ann Surg 1962; 156: 337-55.

26.    Kuss R, Legrain M, Mathe G, Nedey R, Camey M. Homologous human kidney transplantation: experience with six patients. Postgrad Med J 1962; 38: 528-31.

27.    Hamburger J. 11 attempts at renal homotransplants in man after irradiation of the receiver. Revista medica de Chile 1963; 91: 446-59.

28.    Waer M, Vanrenterghem Y, Roels L, Verberckmoes R, Hauglustaine D, van der Schueren E, et al. Renal cadaveric transplantation in diabetics using total lymphoid irradiation or cyclosporin A: A controlled randomized study. Transpl Int 1988; 1: 64-8.

29.    Rowntree LG, Greene CH. The treatment of patients with Addison's disease with the" cortical hormone" of Swingle and Pfiffner. Science 1930; 72: 482-3.

30.    Hench PS, Kendall EC. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181-97.

31.    GOODWIN WE, MIMS MM, KAUFMAN JJ. Human renal transplantation III. Technical problems encountered in six cases of kidney homotransplantation. Trans Am Assoc Genitourin Surg 1962; 54: 116-25.

32.    Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet  1963; 117: 385-95.

33.    Schwartz R, Dameshek W, Donovan J. The effects of 6-mercaptopurine on homograft reactions. J Clin Invest 1960; 39: 952-8.

34.    Calne RY, Alexandre GP, Murray JE. A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann N Y Acad Sci 1962; 99: 743-61.

35.    Bush WW. Overview of transplantation immunology and the pharmacotherapy of adult solid organ transplant recipients: focus on immunosuppression. AACN Clin Issues 1999; 10: 253-69.

36.    Borel JF. Ciclosporin and its future. In: Ciclosporin. Karger Publishers; 1986

37.    Calne RY, Rolles K, Thiru S, McMaster P, Craddock GN, Aziz S, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. The Lancet 1979; 314: 1033-6.

38.    Calne RY, Thiru S, McMaster P, Craddock GN, White DJ, Evans DJ, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. 1978. Am Soc Nephrol 1998; 9: 1751-6.

39.    Cyclosporin a as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Preliminary results of a European multicentre trial. Lancet 1982; 2: 57-60.

40.    Solez K, Vincenti F, Filo RS. Histopathologic Findings From 2-Year Protocol Biopsies From A Us Multicenter Kidney Transplant Trial Comparing Tacrolimus Versus Cyclosporine: A Report Of The Fk506 Kidney Transplant Study Group1, 2, 7. Transplantation 1998; 66: 1736-40.

41.    Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation 2004; 77: 769-76.

42.    McCormack PL. Extended-release tacrolimus: a review of its use in de novo kidney transplantation. Drugs 2014; 74: 2053-64.

43.    Behrend M. A review of clinical experience with the novel immunosuppressive drug mycophenolate mofetil in renal transplantation. Clin Nephrol 1996; 45: 336-41.

44.    Danovitch GM. Mycophenolate mofetil in renal transplantation: Results from the US randomized trials. Kidney Int Suppl 1995: 52: S93-6.

45.    Mycophenolate Mofetil Acute Renal Rejection Study Group. Mycophenolate mofetil for the treatment of a first acute renal allograft rejection: three-year follow-up. The Mycophenolate Mofetil Acute Renal Rejection Study Group. Transplantation 2001; 71: 1091-7.

46.    Calne RY, Lim S, Samaan A, Collier DS, Pollard SG, White DJ, et al. Rapamycin for immunosuppression in organ allografting. Lancet 1989; 334: 227.

47.    Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989; 17: 609.

48.    Neumayer HH, Paradis K, Korn A, Jean C, Fritsche L, Budde K, et al. Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol 1999; 48: 694-703.

49.    Kumar J, Bridson JM, Sharma A, Halawa A. Systematic review on role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors in renal transplant: challenges and window to excel. Exp Clin Transplant  2017; 15: 241-52.

50.    Cosimi AB, Wortis HH, Delmonico FL, Russell PS. Randomized clinical trial of antithymocyte globulin in cadaver renal allograft recipients: importance of T cell monitoring. Surgery 1976; 80: 155-63.

51.    Thiyagarajan UM, Ponnuswamy A, Bagul A. Thymoglobulin and its use in renal transplantation: a review.  Am J Nephrol 2013; 37: 586-601.

52.    Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495-7.

53.    Cosimi AB, Burton RC, Colvin RB, Goldstein GI, Delmonico FL, LaQuaglia MP, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981; 32: 535-9.

54.    Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP. CHIB 201 International Study Group. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193-8.

55.    Hong JC, Kahan BD. Use of anti-CD25 monoclonal antibody in combination with rapamycin to reduce or eliminate cyclosporine treatment during the induction phase of immunosuppression. Transplantation 1999; 68: 701-4.

56.    Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999; 68: 1613-6.

57.    Knechtle SJ, Fernandez LA, Pirsch JD, Becker BN, Chin LT, Becker YT, et al. Campath-1H in renal transplantation: The University of Wisconsin experience. Surgery 2004; 136: 754-60.

58.    Kaufman DB, Leventhal JR, Axelrod D, Gallon LG, Parker MA, Stuart FP. Alemtuzumab induction and prednisone‐free maintenance immunotherapy in kidney transplantation: Comparison with basiliximab induction—Long‐term results. Am J Transplant 2005; 5: 2539-48.

59.    Ciancio G, Burke GW, Gaynor JJ, Roth D, Kupin W, Rosen A, et al. A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow‐up. Clin Transplant 2008; 22: 200-10.

60.    Pascual J, Pirsch J, Torrealba J, Djamali A, Leverson G, Singh N, et al. Antibody-mediated rejection (AMR) in renal allograft recipients treated with alemtuzumab induction. Am J Transplant 2008; 8: 237

61.    Coiffier B, Haioun C, Ketterer N, Engert AA, Tilly H, Ma D, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Am Soc Hematol 1998; 92: 1927-32.

62.    Becker YT, Becker BN, Knechtle SJ, Odorico JS, D'Alessandro AM, Pirsch JD, et al. Treatment Of Steroid Resistant Rejection With A Novel Anti B-Cell Preparation, Rituximab.: Abstract# 964. Transplantation 2000; 69: S362.

63.    Tanabe K, Ishida H, Inui M, Okumi M, Shirakawa H, Shimizu T, et al. ABO-incompatible kidney transplantation: long-term outcomes. Clin Transpl 2013: 307-12.

64.    Ejaz NS, Shields AR, Alloway RR, Sadaka B, Girnita AL, Mogilishetty G, et al. Randomized Controlled Pilot Study of B Cell–Targeted Induction Therapy in HLA Sensitized Kidney Transplant Recipients. Am J Transplant 2013; 13: 3142-54.

65.    Trappe R, Hinrichs C, Appel U, Babel N, Reinke P, Neumayer HH, et al. Treatment of PTLD with rituximab and CHOP reduces the risk of renal graft impairment after reduction of immunosuppression. Am J Transplant 2009; 9: 2331-7.

66.    Malvezzi P, Jouve T, Rostaing L. Costimulation blockade in kidney transplantation: an update. Transplantation 2016; 100: 2315-23.

67.    Harland R, Klintmalm G, Yang H, Jensik S, Shah T, West-Thielke P, Shihab F, Zhang W, Santos V, Tainaka R, Wang X, First R, Holman J. ASKP1240 in De Novo Kidney Transplant Recipients [abstract]. Am J Transplant 2015; 15 (suppl 3).

68.    Nashan B, Tedesco H, Van den Hoogen MW, Berger SP, Cibrik D, Mulgaonkar S, et al. CD40 inhibition with CFZ533-a new, fully human, non-depleting, Fc silent mAB-improves renal allograft function while demonstrating comparable efficacy vs. tacrolimus in de-novo CNI-free kidney transplant recipients. Transplantation 2018; 102: S366.

69.    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906-17.

70.    Raghavan R, Jeroudi A, Achkar K, Gaber AO, Patel SJ, Abdellatif A. Bortezomib in kidney transplantation. J Transplant 2010; 2010: 698594.

71.    Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, et al. Bortezomib provides effective therapy for antibody-and cell-mediated acute rejection. Transplantation 2008; 86: 1754-61.

72.    Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R. FDA report: eculizumab (Soliris®) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. The Oncologist 2008; 13: 993-1000.

73.    Kant S, Bhalla A, Alasfar S, Alachkar N. Ten-year outcome of Eculizumab in kidney transplant recipients with atypical hemolytic uremic syndrome–a single center experience. BMC Nephrol 2020; 21: 1-6.

74.    Yelken B, Arpalı E, Görcin S, Kocak B, Karatas C, Demiralp E, et al. Eculizumab for treatment of refractory antibody-mediated rejection in kidney transplant patients: a single-center experience. Transplant Proc 2015; 47: 1754-9.

75.    Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody‐mediated rejection in sensitized renal transplant recipients. Am J Transplant 2011; 11: 2405-13.

76.    Berger M, Lefaucheur C, Jordan SC. Update on C1 esterase inhibitor in human solid organ transplantation. Transplantation 2019; 103: 1763-75.

77.    Kaplan AP. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol 2010; 126: 918-25.

78.    Huang E, Vo A, Choi J, Ammerman N, Lim K, Sethi S, et al. Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients. Clin J Am Soc Nephrol 2020; 15: 109-16

79.    Viglietti D, Gosset C, Loupy A, Deville L, Verine J, Zeevi A, et al. C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study. Am J Transplant 2016; 16: 1596-603.

80.    Bartko J, Schoergenhofer C, Schwameis M, Firbas C, Beliveau M, Chang C, et al. A randomized, first‐in‐human, healthy volunteer trial of sutimlimab, a humanized antibody for the specific inhibition of the classical complement pathway. Clin Pharmacol Ther 2018; 104: 655-63.

81.    Nikitin PA, Rose EL, Byun TS, Parry GC, Panicker S. C1s inhibition by BIVV009 (Sutimlimab) prevents complement-enhanced activation of autoimmune human B cells in vitro. J Immunol 2019; 202: 1200-9.

82.    Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, et al. Assessment of Tocilizumab (Anti–Interleukin‐6 Receptor Monoclonal) as a potential treatment for chronic antibody‐mediated rejection and transplant glomerulopathy in HLA‐sensitized renal allograft recipients. Am J Transplant 2017; 17: 2381-9.

83.    Pottebaum AA, Venkatachalam K, Liu C, Brennan DC, Murad H, Malone AF, et al. Efficacy and safety of tocilizumab in the treatment of acute active antibody-mediated rejection in kidney transplant recipients. Transplant Direct 2020; 6: e543.

84.    Abou‐El‐Enein M, Volk HD, Reinke P. Clinical development of cell therapies: setting the stage for academic success. Clin Pharmacol Ther 2017; 101: 35-8.

85.    Chhabra AY, Leventhal J, Merchak AR, Ildstad S. HSCT-based approaches for tolerance induction in renal transplant. Transplantation 2017; 101: 2682-90.

86.    Zwang NA, Leventhal JR. Cell therapy in kidney transplantation: focus on regulatory T cells. Am J Nephrol 2017; 28: 1960-72.

87.    Tang Q, Vincenti F. Transplant trials with Tregs: perils and promises. J Clin Invest 2017; 127: 2505-12.

88.    Casiraghi F, Perico N, Gotti E, Todeschini M, Mister M, Cortinovis M, et al. Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration. Stem Cells Transl Med 2020; 9: 427-32.

89.    Jordan SC, Lorant T, Choi J, Kjellman C, Winstedt L, Bengtsson M, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med 2017; 377: 442-53.

90.    Waer M, Vanrenterghem Y, Roels L, Verberckmoes R, Hauglustaine D, van der Schueren E, et al. Renal cadaveric transplantation in diabetics using total lymphoid irradiation or cyclosporin A: A controlled randomized study. Transpl Int 1988; 1: 64-8.

91.    Lui SF, Sweny P, Scoble JE, Varghese Z, Moorhead JF, Fernando ON. Low-dose vs high-dose intravenous methylprednisolone therapy for acute renal allograft rejection in patients receiving cyclosporin therapy.  Nephrol Dial Transplant 1989; 4: 387-9.

92.    Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, et al. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation 2001; 72: 845-50.

93.    Woodle ES, Peddi VR, Tomlanovich S, Mulgaonkar S, Kuo PC, TRIMS Study Investigators. A prospective, randomized, multicenter study evaluating early corticosteroid withdrawal with Thymoglobulin® in living‐donor kidney transplantation. Clin Transplant 2010; 24: 73-83.

94.    Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225-32.

95.    Browne BJ. The tricontinental mycophenolate mofetil trial. Transplantation 1996; 62: 1697.

96.    Behrend M, Grinyo J, Vanrenterghem Y, Rodicio J, Albrechtsen D, Sadek S, et al. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation 1999; 68: 391-6.

97.    Meier-Kriesche HU, Steffen BJ, Hochberg AM, Gordon RD, Liebman MN, Morris JA, et al. Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration1. Transplantation 2003; 75: 1341-6.

98.    Rosenthal JT, Hakala TR, Iwatsuki S, Shaw Jr BW, Starzl TE. Cadaveric renal transplantation under cyclosporine-steroid therapy. Surg Gynecol Obstet 1983; 157: 309-15.

99.    Claes K, Meier-Kriesche HU, Schold JD, Vanrenterghem Y, Halloran PF, Ekberg H. Effect of different immunosuppressive regimens on the evolution of distinct metabolic parameters: evidence from the Symphony study. Nephrol Dial Transplant 2012; 27: 850-7.

100.  Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005; 331: 810.

101.  Jordan ML, Naraghi R, Shapiro R, Smith D, Vivas CA, Scantlebury VP, et al. Tacrolimus rescue therapy for renal allograft rejection–five-year experience. Transplantation 1997; 63: 223-8.

102.  Margreiter R, Pohanka E, Sparacino V, Sperschneider H, Kunzendorf U, Huber W, et al.  European Switch to Tacrolimus Study Group. Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin‐related side‐effects. Transpl Int 2005; 18: 816-23.

103.  Johnson C, Ahsan N, Gonwa T, Halloran P, Stegall M, Hardy M, et al. Randomized Trial Of Tacrolimus (Prograf) In Combination With Azathioprine Or Mychophenolate Mofetil Versus Cyclosporine (Neoral) With Mycophenolate Mofetil After Cadaveric Kidney Transplantation1, 2. Transplantation 2000; 69: 834-41.

104.  Pascual J, Galeano C, Royuela A, Zamora J. A systematic review on steroid withdrawal between 3 and 6 months after kidney transplantation. Transplantation 2010; 90: 343-9.

105.  Merion RM. 2009 SRTR Report on the State of Transplantation. Am J Transplant 2010; 10: 959–60.

106.  Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, et al. Sirolimus in association with mycophenolatemofetil induction for the prevention of acute graft rejection in renal allograft Recipients12. Transplantation 2000; 69: 1252-60.

107.  Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine1. Transplantation 2002; 74: 1070-6.

108.  Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, et al. A phase III study of belatacept‐based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535-46.

109.  Grinyó JM, Gil‐Vernet S, Cruzado JM, Caldés A, Riera L, Serón D, et al. Calcineurin inhibitor‐free immunosuppression based on antithymocyte globulin and mycophenolatemofetil in cadaveric kidney transplantation: results after 5 years. Transpl Int 2003; 16: 820-7.

110.  Srinivas TR, Schold JD, Guerra G, Eagan A, Bucci CM, Meier‐Kriesche HU. Mycophenolatemofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant 2007; 7: 586-94.

111.  Flechner SM, Glyda M, Cockfield S, Grinyó J, Legendre C, Russ G, et al. The ORION study: comparison of two sirolimus‐based regimens versus tacrolimus and mycophenolatemofetil in renal allograft recipients. Am J Transplant 2011; 11: 1633-44.

112.  Hahn D, Hodson EM, Hamiwka LA, Lee VW, Chapman JR, Craig JC, et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev 2019; 12: CD004290

113.  Mjörnstedt L, Schwartz Sørensen S, von ZurMühlen B, Jespersen B, Hansen JM, Bistrup C, et al. Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation. Transpl Int 2015; 28: 42-51.

114.  Mjörnstedt L, Sørensen SS, von zurMühlen B, Jespersen B, Hansen JM, Bistrup C, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant 2012; 12: 2744-53.

115.  Budde K, Rath T, Sommerer C, Haller H, Reinke P, Witzke O, et al. Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study. Clin. Nephrol 2015; 83: 11-21.

116.  Holdaas H, Rostaing L, Serón D, Cole E, Chapman J, Fellstrøm B, et al. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation 2011; 92: 410-8.

117.  Guerra G, Ciancio G, Gaynor JJ, Zarak A, Brown R, Hanson L, et al. Randomized trial of immunosuppressive regimens in renal transplantation. Am J Nephrol 2011; 22: 1758-68.

118.  Carmellini M, Garcia V, Wang Z, Vergara M, Russ G. Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial. J Nephrol 2015; 28: 633-9.

119.  Ponticelli C, Salvadori M, Scolari MP, Citterio F, Rigotti P, Veneziano A, et al. Everolimus and minimization of cyclosporine in renal transplantation: 24-month follow-up of the EVEREST study. Transplantation 2011; 91: e72-3.

120. Pascual J, Berger SP, Witzke O, Tedesco H, Mulgaonkar S, Qazi Y, et al. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. Am J Nephrol 2018; 29: 1979-91.

121. Sommerer C, Suwelack B, Dragun D, Schenker P, Hauser IA, Witzke O, et al. An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients. Kidney Int 2019; 96: 231-44.

122. Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, et al. A phase III study of belatacept‐based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535-46.

123. Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT‐EXT study). Am J Transplant 2010; 10: 547-57.

124. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med 2016; 374: 333-43.

125. Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Grinyó J, Neumayer HH, et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011; 91: 976-83.

126. Ali H, Soliman KM, Shaheen I, Kim JJ, Kossi ME, Sharma A, et al. Rabbit anti-thymocyte globulin (rATG) versus IL-2 receptor antagonist induction therapies in tacrolimus-based immunosuppression era: a meta-analysis. Int J Nephrol 2020; 52: 791-802.

127. Brennan DC, Schnitzler MA. Long-term results of rabbit antithymocyte globulin and basiliximab induction. N Engl J Med 2008; 359: 1736-8.

128. Liu Y, Zhou P, Han M, Xue CB, Hu XP, Li C. Basiliximab or antithymocyte globulin for induction therapy in kidney transplantation: a meta-analysis. Transplant Proc 2010; 42: 1667- 70.

129. Brokhof MM, Sollinger HW, Hager DR, Muth BL, Pirsch JD, Fernandez LA, et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients. Transplantation 2014; 97: 612-7.

130. Sautenet B, Blancho G, Büchler M, Morelon E, Toupance O, Barrou B, et al. One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation 2016; 100: 391-9.

131. Bailly E, Ville S, Blancho G, Morelon E, Bamoulid J, Caillard S, et al. An extension of the RITUX‐ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody‐mediated rejection after renal transplantation. Transpl Int 2020; 33: 786-95.

132. Macklin PS, Morris PJ, Knight SR. A systematic review of the use of rituximab for the treatment of antibody-mediated renal transplant rejection. Transplant Rev 2017; 31: 87-95.

133. Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M. et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. Am J Nephrol 2018; 29: 591-605.

134. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: Am J Transplant 2009; 9: S1-55.

135. Hellemans R, Bosmans JL, Abramowicz D. Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti‐IL 2 Receptor Monoclonal Antibodies? Am J Transplant 2017; 17: 22-7.

136. Cooper DK, Ekser B, Ramsoondar J, Phelps C, Ayares D. The role of genetically engineered pigs in xenotransplantation research. J Clin Pathol 2016; 238: 288-99.

137. U.S. surgeons successfully test pig kidney transplant in human patient. [Online] [Cited 2021 Nov 19]. Available from: URL: https://www.reuters.com/business/healthcarepharmaceuticals/us-surgeons-successfully-test-pig-kidneytransplant-human-patient.

138.  Zhang YS, Yue K, Aleman J, Mollazadeh-Moghaddam K, Bakht SM, Yang J, et al .3D bioprinting for tissue and organ fabrication. Ann Biomed Eng 2017; 45: 148-63.

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