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The first non-invasive device to detect kidney reflux in children

Periodic Reporting for period 2 - Kite (The first non-invasive device to detect kidney reflux in children)

Berichtszeitraum: 2021-09-01 bis 2023-08-31

Kite Medical is developing the first safe, non-invasive and easy-to-use VUR detection method without radiation or trauma. Vesicoureteral reflux (VUR) is the most common urinary tract abnormality in babies and children up to five years. Progression of VUR is associated with complications including permanent kidney scarring, raised blood pressure (hypertension), and in some cases, the kidney stops functioning permanently (end-stage renal disease (ESRD)). In one study, VUR was the single leading cause of kidney damage, accounting for 25% of all children without kidney function that require a transplant or dialysis (Ardissino, Get al. J Urol 2004).
Early diagnosis is vital, but current diagnostic techniques are invasive and either involve radiation exposure or are unreliable. The gold standard voiding cystourethrogram (VCUG) is traumatising and painful for the child and is stressful for parents and clinicians. The VCUG requires children to undergo urethral catheterisation, radiation exposure (children have a greater radio-sensitivity to radiation due to growing tissues and children’s longer life expectancy) and forced bladder filling and emptying while awake. Behaviours of children after a VCUG are consistent with symptoms related to post-traumatic stress disorder. A VCUG procedure is challenging to carry out and may not reflect actual VUR severity. Furthermore, referral to radiology delays treatment and increases costs. Ultrasound does not carry such risks, however, the Cochrane database study (Shaikh et al. 2016 ) has reinforced the previously well-known fact that ultrasound is a poor screening test for VUR (sensitivity =44%).
Clinicians have raised concerns about the low sensitivity of ultrasound and low compliance rate for VCUG tests due to the traumatic nature of the procedure and that children with VUR may not be diagnosed in a timely manner.

The goals of the Kite Medical project are:
• To be the first safe, non-invasive and easy-to-use VUR detection method without radiation exposure and trauma;
• To disrupt the current patient care pathway, by offering physicians a point of care option for detecting VUR, transferring care from the radiology department to primary care settings and
• To facilitate early diagnosis and simple follow-up of VUR to avoid preventable, long term kidney damage due to unnecessary disease progression.

The objectives of the EU-funded project were to advance the technology to limit the impact of motion on the signal and to subsequently evaluate the clinical performance of a prototype system.
A review of the state of the art in bioimpedance was conducted in light of the signal noise observed during a clinical evaluation in 2018/19. The review determined that hardware improvements and a 3D electrode arrangement to allow 3D electrical impedance tomography (3D EIT) could improve the signal to noise ratio (SNR). EIT uses impedance values to create a tomographic image, where electrode arrays around the regions of interest generate 3D images and provide a more accurate representation of changes in the kidneys and bladder. The company hired an EIT expert as CTO to advance the technology to a 3D EIT system.
The Kite system includes hardware, firmware and software elements under development in accordance with medical device standards and includes features to improve the SNR. The advance to 3D EIT has resulted in a significantly improved system that incorporates more electrodes and complementary sensors to detect shape and movement. The data collated during the project has been used to develop proprietary algorithms to improve the measurement quality to account for noise due to motion and other sources. Different noise sources were classified and novel filtering strategies were developed to address the different types of noise and improve signal quality.
To effectively assess the suitability of the 3D EIT system, a preclinical study was conducted. A VUR model was created in pigs by stenting the bladder-ureter junction and fluoroscopy confirmed the presence of VUR. Multiple runs were performed with and without forced movement. The analysis of EIT and motion sensor data indicates that VUR is identifiable. Forced movement of the pig’s leg was not detrimental to this outcome. Many important lessons were learned from this study. The effort put into planning, executing and data analysis for the trial clarified the next steps for the Kite project and to enable the system to be evaluated in a clinical study. Namely, to (1) improve the usability of the hardware and software, (2) modify the instruments to improve data quality, (3) adjust experimental procedures to capture reliable/evaluable data, and (4) adapt the existing system to address privacy concerns in a human clinical trial while maintaining key information that  corroborate procedure and event timing. 
One of the methods used to improve the signal quality during the development process was to design an electrical circuit that minimises the effect of DC common-mode voltage on the useful AC signal in an EIT measurement. The Kite team filed a patent application in August 2022 on an invention relating to a device, a system, and a method for minimising the common-mode signal in an electrical impedance tomography (EIT) instrument.
3D EIT is the current state of the art in bioimpedance for lung function and bladder monitoring. To date, it has not been used to monitor changes in the kidneys. With the addition of complementary sensors to measure motion and sophisticated algorithms to filter and analyse the impedance data, the Kite system was intended to address the technical challenge of detecting VUR and minimising the impact from external noise in the signal.
In EIT, stimulation patterns highly influence the attainable spatial resolution and distinguishability in a reconstruction. Typically, these patterns are decided based on personal experiences and simulations. The Kite team proposed a methodology to select stimulation patterns such that high quality reconstructions were obtained in the region of interest (ROI - in VUR, the ROIs are the kidneys and bladder). The proposed method identifies an optimal set from all possible combinations of stimulation patterns for a fixed number of electrodes. The reconstructions using the optimal set achieve better localisation within the region of interest compared to the common stimulation patterns.
The filtering and characterisation techniques developed to enhance the signal quality used proprietary algorithms and methods developed by the team. Additionally, the signal quality was further improved by designing an electrical circuit that minimises the effect of DC common-mode voltage on the useful AC signal in the Kite EIT measurement.
The Kite project advanced the EIT system design as well as the techniques for signal processing.
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