The effect of rapamycin on renal function in the rat: a comparative study with cyclosporine

Whiting, P. H.; Adam, Birgit; Woo, Jacky; Hasan, Nazmul; Thomson, Angus W.

doi:10.1016/0378-4274(91)90171-2

Cited by 18 publications

(6 citation statements)

References 14 publications

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“…At the University of Alberta and the University of Colorado, the use of SRL was implemented in a substantial number of patients undergoing OLT prior to the FDA black box label and in selected patients thereafter to reduce side‐effects related to CNI therapy, or as an antitumor agent in those with hepatocellular carcinoma [28,42,43]. As SRL has a different safety profile than CNI, the possible advantages of its use must be weighed against a range of other side‐effects such as peripheral swelling, joint pain, wound infections, hyperlipidemia, oral and gastrointestinal ulcerations [44], dermatitis, interstitial pneumonitis [45–47] and possibly vascular thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients

Molinari

Berman

Meeberg

et al. 2010

Transplant International

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Summary The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient‐ and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient‐ and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.

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Section: Discussionmentioning

confidence: 99%

Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients

Molinari

Berman

Meeberg

et al. 2010

Transplant International

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“…RAPA's effect on renal function has been characterized inpeclinical models, particularly the mouse [S, 111 and rat [6,8,9,[21][22][23]. RAPA had little or no effect vh renal function and histopathology in the mouse [5, 111, Sprague-Dawley rat [8,9,21,221, Lewis rat [9,23], and female spontaneously hypertensive rat (SHR) [6]. In the male SHR, RAPA caused renal dysfunction and histopathologic alterations, but at doses 25-100 times higher than the therapeutic doses established for RAPA [9].…”

Section: Introductionmentioning

confidence: 99%

Renal effects of rapamycin in the spontaneously hypertensive rat

DiJoseph¹,

Mihatsch

Sehgal³

1994

Transpl Int

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The effects of rapamycin (RAPA), administered at therapeutic doses, were investigated in the spontaneously hypertensive rat (SHR). Additionally, the reversibility of RAPA's renal effects was investigated at a supratherapeutic dose. At doses that were active in preventing heart and kidney allograft rejection in the rat (0.01-0.08 mg/kg i.v.), RAPA had no effect on kidney function or rat body weight gain. At higher doses (0.8 mg/kg), RAPA produced significant changes in kidney function parameters and caused a loss in body weight. Histopathologic changes, including necrotizing vasculopathy and tubular atrophy, were noted at therapeutic doses. The effects of RAPA on kidney function were completely reversible after a 2-week washout period, though the histopathologic changes were still evident. These studies demonstrate that RAPA does not impair kidney function at therapeutic doses when administered for 2 weeks but does appear to accelerate the naturally occurring renal lesions of the SHR.

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“…These results are underscored by studies in which podocyte‐specific interruption of mTORC1 function leads to glomerular disease and proteinuria . However, in several animal studies, rapamycin did not affect normal kidney function, haemodynamics or histopathology . Rapamycin causes nephrotoxicity that is strain and species‐dependent…”

Section: Discussionmentioning

confidence: 99%

“…26 However, in several animal studies, rapamycin did not affect normal kidney function, haemodynamics or histopathology. 27,28 Rapamycin causes nephrotoxicity that is strain and species-dependent. 12 In addition to the results of GFR, the sodium excretion data in this study are in agreement with studies in which rapamycin However, increased sodium excretion alone is not the most reliable indicator of renal function deterioration, but the sequential sodium fractional excretion increase associated with decreased creatinine clearance is an indicator of renal function deterioration.…”

Section: Ischaemiamentioning

confidence: 99%

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

Alshaman

Truong

Oyekan

2016

Clin Exp Pharma Physio

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Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischaemia-reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR-induced kidney injury. In euvolemic anaesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121 ± 2 to 144 ± 3 mmHg; P<.05), decreased glomerular filtration rate (GFR; 1.6 ± 0.3 to 0.5 ± 0.2 mL/min; P<.05) and increased urinary sodium excretion (UNaV; 14 ± 1 to 109 ± 25 mmol/L per hour; P<.05). In rats subjected to IR, autophagy induction, p-mTOR expression and serum creatinine increased (1.9 ± 0.2 to 3 ± 0.3 mg/dL; P<.05); treatment with rapamycin blunted p-mTOR expression but further increased autophagy induction and serum creatinine (3 ± 0.3 to 5 ± 0.6 mg/dL; P<.05). In contrast, clenbuterol, an mTOR activator, blunted the effect of rapamycin on serum creatinine (4 ± 0.6 vs 2.3 ± 0.3 mg/dL; P<.05), autophagy induction and p-mTOR expression. IR also increased 24 hour protein excretion (9 ± 3 to 17 ± 2 mg/day; P<.05) and kidney injury molecule-1 (KIM-1) expression, and rapamycin treatment further increased KIM-1 expression. Clenbuterol exacerbated protein excretion (13 ± 2 to 26 ± 4 mg/day; P<.05) and antagonized the effect of rapamycin on KIM-1 expression. Histopathological data demonstrated kidney injury in IR rats that was worsened by rapamycin treatment but attenuated by clenbuterol treatment. Thus, mTOR signalling is crucial for normal kidney function and protecting the kidney against IR injury through autophagy suppression.

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The effect of rapamycin on renal function in the rat: a comparative study with cyclosporine

Cited by 18 publications

References 14 publications

Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients

Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients

Renal effects of rapamycin in the spontaneously hypertensive rat

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

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