Evaluation of Acute and Chronic Nephrotoxicity in Acute Lymphatic Leukemia Patients Using Ultrasound Localization Microscopy

Обзор

With increasing survival rates in pediatric oncology, reports of long-term side effects persisting decades after treatment are also rising. Clinically evident nephropathies occur in about 5.5% of survivors more than five years after therapy. Chemotherapeutic agents such as ifosfamide, cisplatin, and carboplatin, as well as kidney-directed treatments like radiation, surgery, or stem cell transplantation, increase this risk. Acute kidney injury has also been described in association with cyclophosphamide and high-dose methotrexate, which are used in the treatment of acute lymphoblastic leukemia (ALL). Studies show a high prevalence of albuminuria (around 14.5% of childhood cancer survivors), an early marker of kidney damage, while standard parameters like creatinine often become abnormal only at later stages. Leukemia survivors suffer from vascular late effects caused by persistent endothelial damage triggered by cancer therapies such as anthracyclines, cyclophosphamide, and asparaginase, which increase inflammation and thrombosis risk. These vascular changes may also contribute to kidney injury. ULM is a high-resolution ultrasound technique that uses microbubbles to visualize the microvasculature and resolve dynamic blood flow changes with a resolution beyond the diffraction limit. ULM is independent of kidney or liver function, has been applied in various organs, and was recently used for the first time to visualize glomeruli-the smallest functional units of the kidney-in humans. This method enables early detection of glomerular injury as a consequence of vascular damage, even before albuminuria appears, potentially allowing earlier adaptation of follow-up and initiation of treatment. This pilot project focuses on survivors of ALL, as they are the largest and best studied pediatric cancer patient group also regarding late effects and, therefore, a sufficient number of individuals can be expected for his monocentric approach. Vascular functional impairment of the kidney could be detected at an early stage and the follow-up structures and measures such as the early use of nephroprotective drugs could be adapted.

Вмешательства

• Диагностический тест Ultrasound Localization Microscopy (ULM)
  Single Examination: ULM of the kidney after application of a contrast medium (SonoVue®, intravenous).
• Диагностический тест Ultrasound Localization Microscopy (ULM)
  ULM of the kidney after application of a contrast medium (SonoVue®, intravenous) at two different time points: Timepoint 1: Before initiation of therapy, latest day 50 before 1st high-dose methotrexate or cyclophosphamide. Timepoint 2: After termination of intensive treatment (after 6-9 months).
• Диагностический тест Blood sample
  Blood draw (including BB, Diff, Glucose, Na, K, Cl, Ca, LDH, Crea, Cystatin C, Uric Acid, CRP, Albumin, Ferritin, Total Protein) through venous access.
• Диагностический тест Blood sample
  Blood draw (including BB, Diff, Glucose, Na, K, Cl, Ca, LDH, Crea, Cystatin C, Uric Acid, CRP, Albumin, Ferritin, Total Protein) through venous access at Timepoint 1 and 2.
• Диагностический тест Urinanalysis
  Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes.
• Диагностический тест Urinanalysis
  Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes at Timepoint 1 and Timepoint 2.
• Диагностический тест Renal sonography
  Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others.
• Диагностический тест Renal sonography
  Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others at time point 1 and time point 2.

Первичные конечные точки

• CEUS Measurement 1 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 2 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 3 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 4 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 5 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 6 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 7 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 8 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 9 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• CEUS Measurement 10 [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]

Вторичные конечные точки (9)

• Blood Count [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• Urine status [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• RI [Срок оценки: Measurement of proteinuria with protein differentiation]
• Flow velocity [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• Weigth [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• Height [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• BP [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• Electrolytes [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]
• Creatinin and urea level [Срок оценки: Study arm early therapeutic effects: Baseline before day 50 of the therapy and follow up after completion of intensive chemotherapy Study arm late therapeutic effects: Baseline at a single-time point in oncological follow-up care]

Критерии участия

Критерии включения

• Diagnosed acute lymphatic leukemia
• From 3 years to < 18 years
• completed oncological treatment or treatment day < 50 according to therapy protocol and no administration of CPM before first examination.

Критерии исключения

• Known allergic disposition to SonoVue / other contrast agents
• Tattoo in the area of the examination field
• Pregnancy
• Breastfeeding mothers
• Contraindication for the use of Sonovue
• Critical condition
• Known clinically evident renal impairment

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Германия · 1 центр

• Department of Pediatrics and Adolescent Medicine — Erlangen

Идентификаторы

NCT: NCT07313878 · HEALED-ULM

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗