Effect of everolimus on renal function in patients with tuberous sclerosis complex

Evidence from EXIST-1 and EXIST-2

John Bissler, Klemens Budde, Matthias Sauter, David N. Franz, Bernard A. Zonnenberg, Michael D. Frost, Elena Belousova, Noah Berkowitz, Antonia Ridolfi, Kingswood J. Christopher

Research output: Contribution to journalArticle

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Abstract

Background. A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. Methods. The long-Term effects of EVE on renal function (4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results. A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88mL/min/1.73m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. Conclusions. The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients ClinicalTrials.gov identifiers NCT00789828 andNCT00790400.

Original languageEnglish (US)
Pages (from-to)1000-1008
Number of pages9
JournalNephrology Dialysis Transplantation
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2019

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Tuberous Sclerosis
Kidney
Glomerular Filtration Rate
Proteinuria
Angiomyolipoma
Astrocytoma
Everolimus
Lymphangioleiomyomatosis
National Cancer Institute (U.S.)
Therapeutics
Terminology
Chronic Kidney Failure
Creatinine

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

Cite this

Effect of everolimus on renal function in patients with tuberous sclerosis complex : Evidence from EXIST-1 and EXIST-2. / Bissler, John; Budde, Klemens; Sauter, Matthias; Franz, David N.; Zonnenberg, Bernard A.; Frost, Michael D.; Belousova, Elena; Berkowitz, Noah; Ridolfi, Antonia; Christopher, Kingswood J.

In: Nephrology Dialysis Transplantation, Vol. 34, No. 6, 01.06.2019, p. 1000-1008.

Research output: Contribution to journalArticle

Bissler, J, Budde, K, Sauter, M, Franz, DN, Zonnenberg, BA, Frost, MD, Belousova, E, Berkowitz, N, Ridolfi, A & Christopher, KJ 2019, 'Effect of everolimus on renal function in patients with tuberous sclerosis complex: Evidence from EXIST-1 and EXIST-2', Nephrology Dialysis Transplantation, vol. 34, no. 6, pp. 1000-1008. https://doi.org/10.1093/ndt/gfy132
Bissler, John ; Budde, Klemens ; Sauter, Matthias ; Franz, David N. ; Zonnenberg, Bernard A. ; Frost, Michael D. ; Belousova, Elena ; Berkowitz, Noah ; Ridolfi, Antonia ; Christopher, Kingswood J. / Effect of everolimus on renal function in patients with tuberous sclerosis complex : Evidence from EXIST-1 and EXIST-2. In: Nephrology Dialysis Transplantation. 2019 ; Vol. 34, No. 6. pp. 1000-1008.
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abstract = "Background. A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. Methods. The long-Term effects of EVE on renal function (4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results. A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6{\%} and 37.5{\%} of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88mL/min/1.73m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. Conclusions. The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients ClinicalTrials.gov identifiers NCT00789828 andNCT00790400.",
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T2 - Evidence from EXIST-1 and EXIST-2

AU - Bissler, John

AU - Budde, Klemens

AU - Sauter, Matthias

AU - Franz, David N.

AU - Zonnenberg, Bernard A.

AU - Frost, Michael D.

AU - Belousova, Elena

AU - Berkowitz, Noah

AU - Ridolfi, Antonia

AU - Christopher, Kingswood J.

PY - 2019/6/1

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N2 - Background. A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. Methods. The long-Term effects of EVE on renal function (4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results. A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88mL/min/1.73m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. Conclusions. The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients ClinicalTrials.gov identifiers NCT00789828 andNCT00790400.

AB - Background. A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. Methods. The long-Term effects of EVE on renal function (4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results. A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88mL/min/1.73m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. Conclusions. The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients ClinicalTrials.gov identifiers NCT00789828 andNCT00790400.

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