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A review of landmark studies on maintenance immunosuppressive regimens in kidney transplantation Cover

A review of landmark studies on maintenance immunosuppressive regimens in kidney transplantation

Asian Biomedicine
Volume 18 (2024): Issue 3 (June 2024)
By: ,   and    
Open Access
|Jun 2024
Figures & tables

Figures & Tables

Figure 1.

Concept of CNI-sparing strategy. The “early period” denotes interventions applied within 4–6 months after transplantation, while the “late period” refers to interventional timing after that. CNI, calcineurin inhibitor; MPA, mycophenolic acid; mTORi, mammalian target of rapamycin inhibitor.

The diagram outlines four strategies related to Calcineurin Inhibitor (CNI) use in clinical treatment. Each strategy is accompanied by drug combination options and timing notes: 1. **CNI Avoidance**: This strategy starts with avoiding CNI from the beginning ("De novo"). Treatment options listed are: - MPA + Corticosteroid - mTORi + Corticosteroid - mTORi + MPA + Corticosteroid - Belatacept + MPA + Corticosteroid 2. **CNI Withdrawal**: In this case, CNI is used initially and withdrawn either early or late. The accompanying drug therapies are: - MPA + Corticosteroid - mTORi + Corticosteroid 3. **CNI Conversion**: Conversion from CNI to another therapy either early or late. Drug options here are: - mTORi + MPA + Corticosteroid 4. **CNI Minimization**: CNI is reduced either from the beginning, early, or late in the treatment process. Drug therapies include: - Reduced CNI + MPA + Corticosteroid - Reduced CNI + mTORi + Corticosteroid
Table 1.

Example of key randomized controlled trials in maintenance immunosuppression in kidney transplantation and an overview of their outcomes.

The table compares different approaches to calcineurin inhibitor (CNI) management in kidney transplantation: CNI Avoidance: Increased risk of rejection, some studies show better GFR, and a higher risk of graft loss. CNI Withdrawal: Increased rejection risk, some studies show improved GFR and lower viral infection rates. CNI Conversion: Better GFR and lower viral infection rates; some show higher rejection and lower cancer rates. CNI Minimization: Better GFR and some studies show lower viral infection rates. Limitations: Population differences, variable outcomes, treatment protocols, follow-up duration, and control groups differ across studies.
CNI avoidanceCNI withdrawalCNI conversionCNI minimization

  • • ELITE-Symphony [85]

  • • ORION [72]

  • • BENEFIT [103]

  • • SPEISSER [65]

  • • CAESAR [66]

  • • ORION [72]

  • • Creeping Creatinine Study [64]

  • • Rapamune Maintenance Regimen Study [63]

  • • CONVERT [88]

  • • CONCEPT [68]

  • • SMART [70]

  • • Spare the Nephron Study [74]

  • • ZEUS [75]

  • • HERAKLES [77]

  • • ASCERTAIN [73]

  • • ELEVATE [78]

  • • CAESAR [66]

  • • ELITE-Symphony [85]

  • • OPTICEPT [67]

  • • A2309 Study [71]

  • • EVEREST [69]

  • • ASSEST [76]

  • • TRANSFORM [95]

  • ○ Increased risk of rejection [72, 85, 103]

  • ○ Some showed better GFR [103]

  • ○ Some showed increased risk of graft loss [85] (non-belatacept study)

  • ○ Increased risk of rejection [66, 72]

  • ○ Some showed better GFR and lower viral infection rate [63, 64]

  • ○ Better GFR [68, 70, 73, 74, 75, 77, 78, 88]

  • ○ Lower viral infection rate [70, 74, 77, 78, 88]

  • ○ Some showed higher rejection rate and lower cancer rate [68, 75, 78, 88]

  • ○ Better GFR [67, 85]

  • ○ Some showed lower viral infection rate [66, 71, 95]

Limitations in interpretation

  • ❖ The included populations are different among studies, mostly low-to-moderate risk patients.

  • ❖ Different tissue typing, organ allocation system, preformed anti-HLA detection.

  • ❖ Dynamic change of outcomes: Banff classification, eGFR estimation.

  • ❖ Different patient care: target C0 concentration, induction regimen and dose.

  • ❖ Lacking of de novo anti-HLA detection protocol.

  • ❖ Different follow-up duration, time of intervention (conversion and withdrawal).

  • ❖ Different “standard” control group.

[i] C0, pre-dose concentration; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HLA, human leukocyte antigen

Table 2.

Summary of modern randomized controlled trials in maintenance immunosuppression in kidney transplantation.

The table summarizes modern randomized controlled trials in kidney transplantation, focusing on different immunosuppressive strategies. Key points include: Studies: ELITE-Symphony, FREEDOM, CONVERT, BENEFIT. Immunosuppressive Protocols: ELITE-Symphony (2007): Examined de novo CNI minimization with varying levels of Tacrolimus (TAC), cyclosporine A (CSA), and Mycophenolate mofetil (MMF) in a study of 1,645 patients. FREEDOM (2008/2012): Compared steroid-free and steroid withdrawal protocols in 337 patients with CSA + basiliximab-based regimens. CONVERT (2009): Examined late conversion from CSA to sirolimus (SRL) in a study of 830 patients, assessing the effect on GFR and graft survival. BENEFIT (2010/2016): Focused on belatacept-based regimens, comparing intensive vs. less-intensive belatacept, showing better patient and graft survival. Findings: ELITE-Symphony: TAC had better GFR and graft survival, but higher diabetes rates. FREEDOM: Steroid withdrawal was associated with no major differences in graft function. CONVERT: SRL conversion led to higher GFR but also higher rejection rates. BENEFIT: Belatacept showed better long-term outcomes compared to CNI, especially in secondary analyses. This provides an overview of how different strategies affect outcomes like GFR, rejection rates, and long-term survival in kidney transplant patients.
Study (year)KTR includedType of studyComparison and target C0 (ng/mL)Allograft function (mean eGFR, mL/min)Acute rejection (%)Patient and graft survivalOther findings
ELITE-Symphony (NEJM 2007) [85]1,645

  • De novo CNI minimization

  • De novo CNI avoidance

  • CsA (relatively higher C0) (150–300 for 3 months then 100–200)

  • CsA (100–200) + daclizumab

  • TAC (3–7) + daclizumab

  • SRL (4–8) + daclizumab

  • (Base: MMF + steroid)

  • TAC was associated with best allograft function.

  • (57, 59, 65, 57)

  • TAC was associated with lowest allograft rejection.

  • (30, 27, 15, 40)

TAC was associated with best allograft survival. Patient survivals were not different.TAC was associated with lowest treatment failure rate.
FREEDOM (AJT 2008) [112]337

  • De novo steroid avoidance

  • Early steroid withdrawal

  • Steroid free

  • Steroid withdrawal on D8

  • Standard steroid (Base: Basiliximab + CsA + MPS)

  • (target C2 CsA 1,500–2,000 ng/mL during month 1, 1,300–1,700 ng/mL during month 2, 1,100–1,500 ng/mL during month 3, 900–1,300 ng/mL during months 4–6 and 800–1,000 ng/mL thereafter)

  • Allograft functions were similar.

  • (56, 55, 59)

  • Steroid-free regimen was associated with the highest incidence of acute rejection, followed by steroid-withdrawal, and standard steroid.

  • (32, 26, 15)

Allograft and patient survival were similar.

  • Steroid-free group used less anti-hyperglycemic medication.

  • Number of KTR diagnosed with diabetes at month 12 was similar between groups.

  • CONVERT (Transplantation 2009) [88]

  • 830

  • Late CNI conversion

  • CNI continuation (CsA C0 50–250 or TAC C0 4–10)

  • CNI conversion to SRL (6–120 months) (C0 8–20)

  • (Base: AZA or MMF + steroids)

  • Overall allograft functions were similar.

  • (61, 64)

  • Acute rejections were similar.

  • (1.5, 3.1)

Allograft and patient survival were similar.

  • Patients with baseline GFR >40 mL/min had significantly higher GFR after SRL conversion.

  • SRL conversion patients with baseline UPCR >1.0 had a higher percentage of UPCR >1.0 at 24 months.

BENEFIT (NEJM 2016) [103]666De novo CNI avoidance

  • More intensive belatacept

  • Less intensive belatacept

  • CsA (150–300 the first month and 100–250 thereafter)

  • (Base: Basiliximab + MMF + glucocorticoids)

  • Belatacept groups were associated with better allograft function.

  • (70, 72, 45)

  • Belatacept groups were associated with higher acute rejections.

  • (24, 18, 11)

The composite of patient and graft survival was better in belatacept group (patient but not graft survival reached significant level in secondary analysis).

  • De novo DSA was significantly lower in belatacept groups.

  • PTLD occurred mainly in EBV negative KTR with more intensive belatacept.

HARMONY (Lancet 2016) [113]587Early steroid withdrawal

  • Basiliximab + standard steroid

  • Basiliximab + steroid withdrawal on D8

  • ATG + steroid withdrawal on D8

  • (Base: advagraf + MMF)

  • (Advagraf target C0 7–12 ng/mL within the first month, 6–10 ng/mL during months 2 and 3, and 3–8 ng/mL during months 4–12)

  • Allograft functions were similar.

  • (46, 47, 50)

  • Acute rejections were similar.

  • (11, 11, 10)

Allograft and patient survival were similar.

  • Incidence of PTDM and osteoporosis were lower in steroid-withdrawal groups.

  • Anemia was more frequent in steroid-withdrawal groups.

TRANSFORM (JASN 2018) [95]2,226De novo CNI minimization

  • EVL (C0 3–8) + minimized TAC (C0 4–7 ng/mL during months 0–2, 2–5 ng/mL during months 3–6, 2–4 ng/mL thereafter) or CsA (C0 100–150 ng/mL, 50–100 ng/mL, and 25–50 ng/mL, respectively)

  • MPA + TAC (C0 8–12 ng/mL during months 0–2, 6–10 ng/mL during months 3–6, and 5–8 ng/mL thereafter) or CsA (C0 200–300 ng/mL, 150–200 ng/mL, and 100–200 ng/mL, respectively)

  • (Base: Basiliximab or ATG + prednisolone)

  • Allograft functions were similar.

  • (53, 54)

  • Acute rejections were similar.

  • (12, 9)

Allograft and patient survival were similar.

  • Discontinuation of study drug was more frequent in the EVL group.

  • Infections occurred less frequently in the EVL group, mainly CMV and BKV.

ATHENA (Kidney Int 2019) [98]655De novo EVL vs. MPA in modern CNI exposure

  • EVL (C0 3–8) + TAC (C0 4–8 until the end of months 2 and 3–5 thereafter)

  • EVL (C0 3–8) + CsA (C0 75–125 until the end of month 2 and 50–100 thereafter)

  • MPA + TAC (C0 4–8 until the end of month 2 and 3–5 thereafter)

  • (Base: Basiliximab + prednisolone)

  • Noninferiority was not shown in primary analysis (eGFR margin = 7 mL/min/1.73 m2).

  • (63, 61, 68)

  • Acute rejections were similar between TAC groups, but was higher in CsA group.

  • (7, 5, 19)

Allograft and patient survival were similar.

  • Drug discontinuation was more frequent in EVL groups.

  • Post hoc analysis showed noninferiority if eGFR margin set at 9 mL/min/1.73 m2.

  • Infections were less frequent in EVL groups, mainly CMV and BKV.

[i] Significant findings are presented in bold.

[ii] ATG, anti-thymocyte globulin; AZA, azathioprine; BENEFIT, Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial; BKV, BK virus; C0, pre-dose concentration; C2, two hours-post-dose concentration; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CONVERT, the Sirolimus Renal Conversion Trial; CsA, cyclosporine A; DSA, donor-specific anti-human leukocyte antigen antibody; EBV, Epstein-Barr virus; eGFR, estimated glomerular filtration rate; ELITE, Efficacy Limiting Toxicity Elimination; EVL, everolimus; GFR, glomerular filtration rate; KTR, kidney transplant recipient; MMF, mycophenolate mofetil; MPA, mycophenolic acid; MPS, mycophenolate sodium; PTDM, post-transplant diabetes mellitus; PTLD, post-transplant lymphoproliferative disorder; SRL, sirolimus; TAC, tacrolimus; TRANSFORM, Transplant Efficacy and Safety Outcomes with an Everolimus-based regimen; UPCR, urine protein-to-creatinine ratio.

DOI: https://doi.org/10.2478/abm-2024-0015 | Journal eISSN: 1875-855X | Journal ISSN: 1905-7415
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Language: English
Page range: 92 - 108
Published on: Jun 28, 2024
Published by: Chulalongkorn University
In partnership with: Paradigm Publishing Services
Keywords:
calcineurin inhibitor nephrotoxicity,
clinical trials,
immunosuppression,
kidney transplantation,
maintenance regimen
Related subjects:
Medicine,
Assistive professions, nursing,
Basic medical science,
Basic medical science, other,
Clinical medicine,
Clinical medicine, other

© 2024 Suwasin Udomkarnjananun, Maaike R. Schagen, Dennis A. Hesselink, published by Chulalongkorn University
This work is licensed under the Creative Commons Attribution 4.0 License.

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