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

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]

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.

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)

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)

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)

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.

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)

De novo DSA was significantly lower in belatacept groups.

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

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)

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

Anemia was more frequent in steroid-withdrawal groups.

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)

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

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

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)

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.