Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites

Anne Robdrup Tinning, Camilla Bengtsen, Niels Viggo Jensen, Lars Bastholt, Boye Lagerbon Jensen, Kirsten Madsen*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor-induced hypertension.

OriginalsprogEngelsk
TidsskriftHypertension
Vol/bind71
Udgave nummer3
Sider (fra-til)473-480
ISSN0194-911X
DOI
StatusUdgivet - mar. 2018

Fingeraftryk

Endothelin-1
Urine
Vascular Endothelial Growth Factor A
Kidney
Creatinine
Brain Natriuretic Peptide
NG-Nitroarginine Methyl Ester
Glomerular Filtration Rate
Epithelial Cells
Proteins

Citer dette

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title = "Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites",
abstract = "Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor-induced hypertension.",
keywords = "Journal Article, Hypertension, Vascular endothelial growth factor A, Nitric oxide, Endothelin-1, Kidney, Prospective Studies, Follow-Up Studies, Humans, Middle Aged, Hypertension/chemically induced, Male, Nitric Oxide/metabolism, Dose-Response Relationship, Drug, Pyrimidines/adverse effects, Time Factors, Carcinoma, Renal Cell/drug therapy, Female, Sulfonamides/adverse effects, Kidney Neoplasms/drug therapy, Glomerular Filtration Rate, Drug Administration Schedule, Risk Assessment, Administration, Oral, Hospitals, University, Neoplasm Invasiveness/pathology, Denmark, Aged, Neoplasm Staging, Cohort Studies",
author = "Tinning, {Anne Robdrup} and Camilla Bengtsen and Jensen, {Niels Viggo} and Lars Bastholt and Jensen, {Boye Lagerbon} and Kirsten Madsen",
note = "{\circledC} 2018 American Heart Association, Inc.",
year = "2018",
month = "3",
doi = "10.1161/HYPERTENSIONAHA.117.10225",
language = "English",
volume = "71",
pages = "473--480",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams & Wilkins",
number = "3",

}

Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites. / Tinning, Anne Robdrup; Bengtsen, Camilla; Jensen, Niels Viggo; Bastholt, Lars; Jensen, Boye Lagerbon; Madsen, Kirsten.

I: Hypertension, Bind 71, Nr. 3, 03.2018, s. 473-480.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites

AU - Tinning, Anne Robdrup

AU - Bengtsen, Camilla

AU - Jensen, Niels Viggo

AU - Bastholt, Lars

AU - Jensen, Boye Lagerbon

AU - Madsen, Kirsten

N1 - © 2018 American Heart Association, Inc.

PY - 2018/3

Y1 - 2018/3

N2 - Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor-induced hypertension.

AB - Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor-induced hypertension.

KW - Journal Article

KW - Hypertension

KW - Vascular endothelial growth factor A

KW - Nitric oxide

KW - Endothelin-1

KW - Kidney

KW - Prospective Studies

KW - Follow-Up Studies

KW - Humans

KW - Middle Aged

KW - Hypertension/chemically induced

KW - Male

KW - Nitric Oxide/metabolism

KW - Dose-Response Relationship, Drug

KW - Pyrimidines/adverse effects

KW - Time Factors

KW - Carcinoma, Renal Cell/drug therapy

KW - Female

KW - Sulfonamides/adverse effects

KW - Kidney Neoplasms/drug therapy

KW - Glomerular Filtration Rate

KW - Drug Administration Schedule

KW - Risk Assessment

KW - Administration, Oral

KW - Hospitals, University

KW - Neoplasm Invasiveness/pathology

KW - Denmark

KW - Aged

KW - Neoplasm Staging

KW - Cohort Studies

U2 - 10.1161/HYPERTENSIONAHA.117.10225

DO - 10.1161/HYPERTENSIONAHA.117.10225

M3 - Journal article

C2 - 29311252

VL - 71

SP - 473

EP - 480

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 3

ER -