The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

Table 3

(a) Effect on renal function of de novo mTOR immunosuppression (b) effect on renal function of converting to sirolimus (c) effect on renal function of converting to everolimus (d) association of mTOR immunosuppression with proteinuria.

(a)

	mTOR  inhibitor	Change in GFR (mL/min/1.73 m^2) after conversion					Change in serum creatinine concentration (mg/dL) after conversion		Change in CrCl (mL/min) from baseline at postconversion time point
		3 months	6 months	1 year	2 years	5 years	6 months	1 year	6 months	1 year
Levy et al. Liver Transpl. 2006; 12: 1640–8 [52]	EVR								EVR: 1, 2, and 4 mg/day versus placebo: −18.7, −36.5, and −33.2 versus −37	EVR: 1, 2, and 4 mg/day versus placebo: −20.2, −43.0, and −36.9 versus −36.9
Chinnakotla et al. Liver Transpl. 2009; 15: 1834–1842 [55]	SRL	−46.5 versus −41.0 (SRL versus TAC)		−39.5 versus −30.0 (SRL versus TAC)	−43.5 versus −31.5 (SRL versus TAC)	−38.5 versus −37.0 (SRL versus TAC)
Campsen et al. J Transplant. 2011; 2011: 913094 [54]	SRL		−2.85 versus −9.66 (CNI versus SRL, 𝑃=0.0465)	−6.29 versus −13.32 (CNI versus SRL, 𝑃=0.0320)
Zimmerman et al. Liver Transpl. 2008; 14: 633–8 [15]	SRL						−0.22 versus +0.61 (SRL versus CNIs, 𝑃=0.0021)	−0.28 versus +0.35 (SRL versus CNIs, 𝑃<0.0001)

𝑃 values are included where available.
CNI: calcineurin inhibitor; CrCl: creatinine clearance; EVR: everolimus; GFR: glomerular filtration rate; mTOR: mammalian target of rapamycin; SRL: sirolimus; TAC: tacrolimus.

(b)

Change in GFR (mL/min/1.73 m^2) after conversion

Change in serum creatinine concentration (µm/L) after conversion

Change in 24 h CrCl (mL/min) after conversion

3 mo

6 mo

1 year

2 years

3 years

1 mo

3 mo

6 mo

1 year

2 years

3 years

3 mo

1 year

Early conversion (≤3 months after transplantation)

McKenna et al. ILTS. 2011 (Abstract O-17) [68]

Rogers et al.  Clin Transplant. 2009; 23: 887–96 [48]

+29.7 versus +18.5 (early versus late conversion, 𝑃<0.05)

+28.7 versus +12.4 (early versus late conversion, 𝑃<0.05)

+25.5 versus +14.7 (early versus late conversion, 𝑃<0.05)

Harper et al. Transplantation. 2011; 91: 128–32 [67]

+10.6 versus baseline (𝑃<0.05)

Schleicher et al. Transplant Proc. 2010; 42: 2572–5 [49]

+15 versus +9 (early versus late conversion, 𝑃=0.04)

+16 versus +10 (early versus late conversion, 𝑃=0.05)

+22^† versus +12^† (early versus late conversion, 𝑃=0.04)

−0.7^‡ (early conversion versus baseline, 𝑃=0.01); −0.6^‡ (late conversion versus baseline, 𝑃=0.05)

Late conversion (>3 months after transplantation)

Campbell et al. Clin Transplant. 2007; 21: 377–84 [71]

0^‡ (SRL versus CNI)

Di Benedetto et al.  Transplant Proc. 2009; 41: 1297–9 [81]

DuBay et al. Liver Transpl. 2008; 14: 651–9 [72]

Herlenius et al. Transplant Proc. 2010; 42: 4441–8 [73]

+12 versus baseline (𝑃=0.03)

Lam et al.  Dig Dis Sci. 2004; 49: 1029–35 [74]

−0.32^‡ versus baseline (𝑃=0.029)

+0.12^‡, versus baseline (𝑃=NS)

Sanchez et al.  Transplant Proc. 2005; 37: 4416–23 [69]

+8.2, 𝑃=0.05 versus case control

+20.2, NS versus case control

+16.1, NS versus case control

−0.1

0

0

Shenoy et al. Transplantation. 2007; 83: 1389-92 [76]

+12 versus −4, NS versus CNI

Uhlmann et al.  Exp Clin Transplant. 2012; 10: 30–8 [77]

+11.9 versus baseline (𝑃<0.05)

−27 versus baseline (𝑃<0.05)

Watson et al. Liver Transpl. 2007; 13: 1694–702 [78]

+7.7 versus baseline (𝑃=0.001)

+6.1 versus baseline (𝑃=0.024)

Abdelmalek et al. Am J Transplant. 2012; 12: 694–705 [45]

−4.45 versus −3.07 (SRL versus CNI, 𝑃=0.34)

Bäckman et al.  Clin Transplant. 2006; 20: 336–9 [82]

+6.4 (𝑃=NS from baseline)

Fairbanks et al.  Liver Transpl. 2003; 9: 1079–85 [83]

+9* versus baseline; (𝑃=0.01)

Nair et al.  Liver Transpl. 2003; 9: 126–9 [84]

−0.45^‡ versus baseline (𝑃=0.001)

Neff et al.  Transplant Proc. 2003; 35: 3029–31 [85]

+11.3 versus baseline

Vivarelli et al. Transplant Proc. 2010; 42: 2579–84 [80]

+18 versus baseline^†

+19 versus baseline^†

+19 versus baseline^†

Wadei et al.  Transplantation. 2012; 93: 1006–12 [86]

+3.5^† versus baseline (𝑃=0.03)

−0.1 versus baseline (𝑃=0.25)

𝑃 values are included where available.
∗Median eGFR, mean of 67 weeks; †mL/min; ‡mg/dL.
CNI: calcineurin inhibitor; CrCl: creatinine clearance; GFR: glomerular filtration rate; mo: month; NS: nonsignificant; SRL: sirolimus.

(c)

	Change in GFR (mL/min/1.73 m^2) after conversion			Change in serum creatinine concentration (µmol/L) after conversion			Change in CrCl (mL/min) from baseline at postconversion time point
	6 months	1 year	Other time points	3 months	6 months	1 year	6 months	1 year
Early conversion (≤3 months after transplantation)
Fischer et al. Am J Transplant. 2012; 12: 1855–65 [50]		11-month data (EVR versus CNI): CG-GFR: mean change from baseline∶+4.4±27.1 versus 0.9±29.2; LS mean difference ±SE: −2.923±3.920(𝑃=0.457)^§; MDRD-GFR: mean change from baseline: +2.0±23.2 versus −2.8±23.1LS mean difference ± SE: −7.778±3.338(𝑃=0.021)^§
Schlitt et al. AASLD 2012 [91]			35 months: difference in eGFR between EVR and CNI: Cockcroft-Gault: −10.5 mL/min (𝑃=0.096) and Nankivell formula: −10.5 mL/min (𝑃=0.015)
Masetti et al. Am J Transplant. 2010; 10: 2252–62 [89]	+6.1 versus −16.5 (EVR versus CsA, 𝑃<0.001 comparison of absolute values)	+5.9 versus −14.8 (EVR versus CsA, 𝑃<0.001 comparison of absolute values)
De Simone et al.  Am J Transplant. 2012; 12: 3008–20 [87]		EVR + TAC-RD (adjusted mean difference in eGFR change for EVR + TAC-RD versus TAC-SD: +8.50±2.12;𝑃<0.001)
Saliba et al. AASLD 2012 [90]			24 months: EVR + TAC-RD versus TAC-SD: mean difference in eGFR change: +6.66 (97.5% CI: +1.9,+11.42;𝑃=0.0018)
Late conversion (>3 months after transplantation)
Castroagudín et al.  Liver Transpl. 2009; 15: 1792–7 [94]	+3.99 (NS versus baseline)	+7.65 (𝑃=0.016 versus baseline)			−0.09 (NS versus baseline)	−0.22^‡ (𝑃<0.05 versus baseline)	+5.18 (NS versus baseline)	+9.82 (𝑃=0.025 versus baseline)
De Simone et al. Transpl Int. 2009; 22: 279–86 [95]								+4.03
De Simone et al. Liver Transpl. 2009; 15: 1262–9 [96]							EVR: +1.0; controls: +2.3 (NS)
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]	+6.6 chronic renal failure subpopulation versus baseline (𝑃=0.0002)	+4.2 overall versus baseline (𝑃=0.007); +8.6 chronic renal failure subpopulation versus baseline (𝑃=0.02)		−11 versus baseline (𝑃=0.04)	−9 versus baseline (𝑃=NS)	−6 versus baseline (𝑃=NS)

𝑃 values are included where available.
∗Median eGFR; ^†mL/min; ^‡mg/dL.
§Between-group difference (calculated as CNI group minus everolimus group) at month 11 after baseline; results based on ANCOVA model.
CG-GFR: GFR calculated with the Cockcroft-Gault formula; CNI: calcineurin inhibitor; CrCl: creatinine clearance; CsA: cyclosporin A; EVR: everolimus; GFR: glomerular filtration rate; LS: least square; MDRD: modification of diet in renal disease; MDRD-GFR: GFR calculated using the MDRD formula; NS: nonsignificant; SE: standard error; TAC-RD: reduced-dose tacrolimus (C0: 3–5 ng/mL); TAC-SD: standard-dose tacrolimus (C0: 6–10 ng/mL).

(d)

	Proteinuria (after conversion unless otherwise stated), % recipients
Sirolimus studies
Early conversion (≤3 months after transplantation)
Harper et al.  Transplantation. 2011; 91: 128–32 [67]	Proteinuria: preconversion: 45; 6 months: 72; 3 years: 63; 5 years: 58
Late conversion (>3 months after transplantation)
DuBay et al.  Liver Transpl. 2008; 14: 651–9 [72]	7 versus 4 (SRL versus CNI)
Herlenius et al.  Transplant Proc. 2010; 42: 4441–8 [73]	8.3 versus 7.7 (SRL versus MMF)
Morard et al.  Liver Transpl. 2007; 13: 658–64 [75]	Albuminuria: 36
Uhlmann et al.  ExpClin Transplant. 2012; 10: 30–8 [77]	Proteinuria increased at 6 months after conversion (𝑃<0.05)
Wadei et al. Transplantation. 2012; 93: 1006–12 [86]	81
Everolimus studies
Early conversion (≤3 months after transplantation)
De Simone et al.  Am J Transplant. 2012; 12: 3008–20 [87]	EVR + TAC-RD versus TAC-SD: 2.9 versus 0.4 (RR: 6.89, 95% CI 0.85, 55.54)
Fischer et al.  Am J Transplant. 2012; 12: 1855–65 [50]	EVR versus CNI: 9.9 versus 2.0
Late conversion (>3 months after transplantation)
Castroagudín et al. Liver Transpl. 2009; 15: 1792–7 [94]	38.1
Saliba et al. Liver Transpl. 2011; 17: 905–13 [98]	5.4
Vallin et al.  Clin Transplant. 2011; 25: 660–9 [99]	13 versus 29 (pre- versus after conversion, 𝑃<0.05)

𝑃 values are included where available.
CNI: calcineurin inhibitor; EVR: everolimus; MMF: mycophenolate mofetil; SRL: sirolimus; RR: relative risk; 95% CI: 95% confidence interval; TAC: tacrolimus; TAC-RD: reduced-dose tacrolimus (C0: 3–5 ng/mL); TAC-SD: standard-dose tacrolimus (C0: 6–10 ng/mL).