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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoblastic Leukaemias (ALL); Long Term Follow-Up
• Intervention / Treatment: Diagnostic test: Ultrasound Localization Microscopy (ULM); Diagnostic test: Ultrasound Localization Microscopy (ULM); Diagnostic test: Blood sample; Diagnostic test: Blood sample; Diagnostic test: Urinanalysis; Diagnostic test: Urinanalysis; Diagnostic test: Renal sonography; Diagnostic test: Renal sonography

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Axel Karow, MD; Phone Number: +4991318533118; Email: axel.karow@uk-erlangen.de
• Study Contact Backup: Name: Alexander Dierl, MD; Phone Number: +4991318533118; Email: alexander.dierl@uk-erlangen.de

Study Locations

• Germany
  • Baveria
    • Erlangen, Baveria, Germany, 91054
      • Recruiting
      • Department of Pediatrics and Adolescent Medicine
      • Contact: Axel Karow, MD; Phone Number: +49 9131 8533118; Email: axel.karow@uk-erlangen.de
      • Contact: Alexander Dierl, MD; Phone Number: +4991318533118; Email: alexander.dierl@uk-erlangen.de
      • Principal Investigator: Axel Karow, MD
      • Principal Investigator: Alexander Dierl, MD
      • Principal Investigator: Eva-Maria Wild, MD
      • Principal Investigator: Henriette Grieshaber Bouyer Mandelbaum, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early therapeutic effects; Diagnosed acute lymphatic leukemia; Treatment day < 50 according to therapy protocol / no administration of CPM before first examination; From 3 years to < 18 years	Diagnostic test: Ultrasound Localization Microscopy (ULM); Single Examination: ULM of the kidney after application of a contrast medium (SonoVue®, intravenous).; Diagnostic test: 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).; Diagnostic test: 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.; Diagnostic test: 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.; Diagnostic test: Urinanalysis; Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes.; Diagnostic test: Urinanalysis; Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes at Timepoint 1 and Timepoint 2.; Diagnostic test: Renal sonography; Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others.; Diagnostic test: Renal sonography; Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others at time point 1 and time point 2.
Experimental: Late therapeutic effects; Diagnosed acute lymphatic leukemia; Completed oncological treatment; From 3 years to < 18 years	Diagnostic test: Ultrasound Localization Microscopy (ULM); Single Examination: ULM of the kidney after application of a contrast medium (SonoVue®, intravenous).; Diagnostic test: 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).; Diagnostic test: 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.; Diagnostic test: 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.; Diagnostic test: Urinanalysis; Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes.; Diagnostic test: Urinanalysis; Examination of urine for erythrocytes, leukocytes, pH value, nitrite, protein, blood, and electrolytes at Timepoint 1 and Timepoint 2.; Diagnostic test: Renal sonography; Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others.; Diagnostic test: Renal sonography; Renal sonography including resistance index (RI), Doppler signal, flow velocity, and others at time point 1 and time point 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CEUS Measurement 1	Peak enhancement (PE)	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	Wash-in area under the curve (WIAUC)	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	Wash-in perfusion index (WiPI)	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	Wash-in rate (WIR)	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	Wash-out under the curve (WoAUC)	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	Wash-in and wash-out under the curve (WiWoAUC)	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	Wash-out rate (WoR)	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	Time to peak (TTP)	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	Rise time (RT)	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	Mean transit time (local) (mTTI)	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 11	Fall time (FT)	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 12	Peak enhancement (PE)	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Count	Complete blood count with number of red and white blood cells and platelets per µl	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	Measurement of proteinuria in mg/l with protein differentiation	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	Resistance index (Sonography)	Measurement of proteinuria with protein differentiation
Flow velocity	Flow velocity in Doppler Signal (Sonography)	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	Weigth of the participant in kilograms	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	Height of the participant in meters	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	Measurement of systolic, diastolic and mean blood pressure in mmHg	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	Concentration of serum electrolytes (Na, K, Cl, Mg, P) in mmol/L.	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	Serum Creatinin and urea level in mg/dl	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

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2025
• Primary Completion (Estimated): November 19, 2026
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: November 18, 2025
• First Submitted That Met QC Criteria: December 22, 2025
• First Posted (Estimated): January 2, 2026

Study Record Updates

• Last Update Posted (Estimated): January 2, 2026
• Last Update Submitted That Met QC Criteria: December 22, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: HEALED-ULM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The raw, individual and identifiable patient data are protected and are not available due to data privacy laws. Further data sets are planned to be shared.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication

IPD Sharing Access Criteria

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request as follows:

Individual participant data will not be available Study Protocol and Statistical Analysis Plan will be available The data will be available beginning 9 months and ending 36 months following article publication.

The data will be available to researchers who provide a methodologically sound proposal.

The data will be available for individual participant data meta-analysis, only. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at https://www.uk-erlangen.de.

Restrictions may apply due to patient privacy and the General Data Protection Regulation.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No