Abstract
mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes.
Highlights
MTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity
One example is the antitumor effect of mTOR inhibitors (mTORi) that has been ascribed to general inhibition of proliferation and to a specific antiangiogenic activity due to reduced production of and response to vascular endothelial growth factor (VEGF)-A resulting in limited blood supply to the tumor[12,13]
The VEGF network is involved in maintaining physiologic functioning of glomeruli and peritubular capillaries[14,15] and has been found to be dysregulated in a large variety of kidney diseases including diabetic nephropathy, glomerulonephritis, thrombotic microangiopathies and chronic allograft nephropathy (CAN) after kidney transplantation[14,15]
Summary
MTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. It had been speculated that mTORi could protect from cardiovascular events and chronic allograft dysfunction through intrinsic mechanisms and by enabling avoidance or at least reduction of nephrotoxic calcineurin inhibitors (CNI) with the final goal of improved long-term graft and patient survival Despite these important advantages, mTORi are frequently withheld or withdrawn since they are perceived as being associated with an unfavorable safety profile limiting their use in many transplant recipients. One example is the antitumor effect of mTORi that has been ascribed to general inhibition of proliferation and to a specific antiangiogenic activity due to reduced production of and response to vascular endothelial growth factor (VEGF)-A resulting in limited blood supply to the tumor[12,13]. VEGF-A has been implicated in proliferation and protection of tubular cells from apoptosis rendering it a survival factor for tubular e pithelium[16] that might act in an autocrine or paracrine manner
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