Immunosuppression Modification by Everolimus With Minimization of Calcineurin Inhibitors Recovers Kidney Graft Function Even in Patients With Very Late Conversion and Also With Poor Graft Function

Nojima, Masanori; Yamada, Yusuke; Higuchi, Y.; Shimatani, K.; Kanematsu, Akihiro; Yamamoto, Shingo

doi:10.1016/j.transproceed.2016.11.018

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…An interaction was observed between baseline proteinuria and time to conversion, and the authors concluded that the success of EVL conversion with CNI elimination depended on not making so late conversions and not converting recipients with high baseline proteinuria. On the other hand, Nojima et al[ 25 ] demonstrated that late immunosuppression conversion, at > 3 years after kidney transplantation, using EVL in addition to a reduction in CNI dose safely and significantly improved graft function.…”

Section: Adverse Eventsmentioning

confidence: 99%

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Introduction of everolimus in kidney transplant recipients at a late posttransplant stage

Uchida

Iwai

Nakatani

2018

WJT

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This minireview focuses on the current knowledge about the introduction of everolimus (EVL), a mammalian target of rapamycin inhibitor, with calcineurin inhibitor (CNI) elimination or minimization in kidney transplant recipients at a late posttransplant stage. Within, we have summarized two major clinical trials, ASCERTAIN and APOLLO, and seven other retrospective or nonrandomized studies. In the open-label multicenter ASCERTAIN study, the estimated glomerular filtration rate (eGFR) at 24 mo after conversion was not significantly different between three groups-EVL with CNI elimination, CNI minimization and continued CNI unchanged-at a mean of 5.4 years after transplantation. However, recipients with baseline creatinine clearance higher than 50 mL/min had a greater increase in measured GFR after CNI elimination. In the open-label multicenter APOLLO study, adjusted eGFR within the on-treatment population was significantly higher in the EVL continuation group than in the CNI continuation group at 12 mo after conversion at a mean of 7 years posttransplantation. Other studies on recipients without adverse events and already having satisfactory renal function showed favorable graft function by EVL late-induction with CNI elimination or reduction. These studies showed that chronic allograft nephropathy, CNI nephrotoxicity, CNI arteriolopathy, cancer and viral infection (especially cytomegalovirus infection) may be good indications for late conversion to EVL.

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Section: Adverse Eventsmentioning

confidence: 99%

“…Chronic allograft nephropathy, CNI nephrotoxicity and CNI arteriolopathy may be good indications for late conversion to EVL[ 20 - 23 , 25 ]. Furthermore, cancer is one of the main indications for late conversion to EVL[ 20 , 21 ].…”

Section: Cause Of Late Conversion To Evlmentioning

confidence: 99%

Introduction of everolimus in kidney transplant recipients at a late posttransplant stage

Uchida

Iwai

Nakatani

2018

WJT

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“…In contrast, Nojima et al reported significant improvement in renal function at 1-year in Japanese KTx patients, including patients with low baseline eGFR (< 30 mL/min) converted to EVR-based regimen at a mean 7.4 years post-transplant. This could be due to the low CNI C 0 levels observed in this study [ 16 ].…”

Section: Discussionmentioning

confidence: 92%

Safety and effectiveness of everolimus in maintenance kidney transplant patients in the real-world setting: results from a 2-year post-marketing surveillance study in Japan

et al. 2021

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Background Data on real-world use of everolimus (EVR) in Japanese maintenance kidney transplant (KTx) patients are limited. This post-marketing surveillance study was conducted to assess the safety and effectiveness of EVR, and identify factors affecting renal impairment. Methods Adult maintenance KTx patients were enrolled within 14 days of initiating EVR. Patient medical data were collected using electronic data capture case report forms at 6 months, 1, and 2 years after initiating EVR, or at discontinuation. Results All patients receiving EVR in Japan during the surveillance period were enrolled (N = 263). Mean time from transplantation to EVR initiation was 75.7 months. Decreased renal function (31.56%) was the primary reason for initiating EVR. In combination with EVR, the mean daily dose of tacrolimus and cyclosporine could be reduced to ~ 79 and ~ 64%, by 2 years, respectively. Incidences of serious adverse events and adverse drug reactions were 15.97 and 49.43%, respectively. Two-year graft survival rate was 95.82% and low in patients with baseline estimated glomerular filtration rate (eGFR; modification of diet in renal disease) < 30 mL/min/1.73 m2 (69.57%; P < 0.0001) and urinary protein/creatinine ratio (UPCR) ≥ 0.55 g/gCr (84.21%; P = 0.0206). Throughout the survey, mean eGFR values were stable (> 55 mL/min/1.73 m2). Renal impairment was influenced by patient and donor age, eGFR, and UPCR at baseline. Conclusions No new safety concerns for the use of EVR in adult maintenance KTx patients were identified. Early EVR initiation may be considered in these patients before renal function deterioration occurs.

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“…One factor that significantly contributes to inferior long‐term renal allograft function is CNI nephrotoxicity (CIN). Therefore, multiple studies have investigated alternative CNI‐free immunosuppressive regimens after renal transplantation . Notably, the CNI‐free regimens using Belatacept have been very encouraging, showing improved graft survival over several years .…”

Section: Introductionmentioning

confidence: 99%

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

et al. 2017

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One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.

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Immunosuppression Modification by Everolimus With Minimization of Calcineurin Inhibitors Recovers Kidney Graft Function Even in Patients With Very Late Conversion and Also With Poor Graft Function

Cited by 5 publications

References 8 publications

Introduction of everolimus in kidney transplant recipients at a late posttransplant stage

Introduction of everolimus in kidney transplant recipients at a late posttransplant stage

Safety and effectiveness of everolimus in maintenance kidney transplant patients in the real-world setting: results from a 2-year post-marketing surveillance study in Japan

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

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