Renal Structural and Functional Alterations Following Repeated Ureteroscopic Procedures: An Exploratory Multimodal Imaging Study (BackFlow2)

Background and Rationale

Retrograde intrarenal surgery (RIRS) and ureteroscopy (URS) are widely used minimally invasive procedures for the treatment of upper urinary tract stones. These procedures require continuous irrigation to maintain endoscopic visibility, which may result in substantial elevations in intrarenal pressure (IRP). Elevated IRP can induce intrarenal backflow (IRB), involving the movement of renal pelvic fluid into the renal parenchyma, venous circulation, lymphatic system, and surrounding interstitial tissue.

Experimental studies have demonstrated that elevated IRP may be associated with intrarenal backflow and renal parenchymal alterations. Previous porcine MRI studies have demonstrated regional distribution of intrarenal backflow, suggesting that pressure-related effects may involve specific anatomical regions of the kidney.

Although the relationship between elevated IRP and infectious complications following ureteroscopy has received increasing attention, the potential long-term structural and functional consequences of repeated ureteroscopic procedures remain insufficiently investigated. In particular, it is unknown whether repeated exposure to elevated intrarenal pressure is associated with persistent regional parenchymal alterations, including fibrosis, atrophy, or impaired renal function.

Study Objectives

The primary objective of BackFlow2 is to investigate potential structural and functional renal alterations in patients with a history of repeated unilateral ureteroscopic procedures for urinary stone disease.

The study aims to:

Assess regional renal parenchymal characteristics using multiparametric magnetic resonance imaging (MRI).

Evaluate renal parenchymal stiffness using ultrasound shear-wave elastography as a potential indicator of fibrotic changes.

Assess split renal function and renal scarring using technetium-99m dimercaptosuccinic acid (⁹⁹ᵐTc-DMSA) scintigraphy.

Compare imaging findings between the previously instrumented kidney and the contralateral kidney within individual participants.

Compare renal imaging parameters and inter-renal differences between patients and healthy controls.

Study Design and Population

BackFlow2 is an exploratory, observational, cross-sectional study conducted at Lillebaelt Hospital, Vejle, Denmark.

The study aims to enrol 20 adult participants, comprising 10 patients with a history of repeated unilateral ureteroscopic procedures and 10 healthy controls.

Eligible patients are aged 18-75 years and must have undergone at least three ureteroscopic procedures (RIRS/URS/URSL) involving the same kidney, with no more than one previous ureteroscopic procedure involving the contralateral kidney. More than one month must have elapsed since the most recent procedure before study examinations.

Healthy controls are aged 35-75 years, have serum creatinine levels within the normal reference range, and have no history of ureteroscopy or known renal disease.

Participants with conditions potentially affecting renal structure or function, or interfering with imaging interpretation, are excluded according to predefined eligibility criteria.

Patients are recruited from the Department of Urology through clinical screening and review of previous ureteroscopic procedures and medical records. Healthy controls are recruited through voluntary participation.

All participants provide written informed consent before undergoing study-specific examinations.

Study Procedures

All participants undergo a multimodal assessment of renal structure and function, comprising serum creatinine measurement, multiparametric MRI, bilateral renal ultrasound elastography, and ⁹⁹ᵐTc-DMSA scintigraphy.

1. Renal Function Assessment

   Serum creatinine is measured before the imaging examinations to assess overall renal function. In healthy controls, serum creatinine within the normal reference range is required to confirm eligibility.

2. Multiparametric Renal MRI

   Renal MRI is performed using a 1.5T Philips Ingenia MRI system without intravenous contrast administration.

   The imaging protocol includes:

   T1 mapping using a gradient-echo turbo field echo (GRE TFE) sequence.

   Heavily T2-weighted three-dimensional coronal imaging using a turbo spin-echo (TSE) sequence.

   Diffusion-weighted imaging (DWI) using single-shot echo-planar imaging (EPI) with 14 b-values.

   T2*-weighted imaging using a gradient-echo (GRE) sequence.

   Renal arterial flow imaging using a gradient-echo (GRE) sequence.

   Both kidneys are examined to assess regional differences in renal parenchymal structure and functional imaging characteristics.

   Regions of interest are defined in selected anatomical regions of both kidneys to facilitate intraindividual and between-group comparisons.

3. Renal Ultrasound Elastography

   Bilateral renal ultrasound shear-wave elastography is performed using a Mindray Resona I9 diagnostic ultrasound system (Mindray, Shenzhen, China) to assess regional renal parenchymal stiffness.

   Three repeated measurements are obtained in each of five predefined anatomical regions per kidney: apical, lateroapical, lateral, lateroinferior, and inferior.

   Regional stiffness measurements are compared between the previously instrumented and contralateral kidneys and between patients and healthy controls.

   Ultrasound elastography is used as a complementary imaging method to investigate potential regional parenchymal alterations associated with fibrosis.

4. Renal DMSA Scintigraphy

Renal scintigraphy is performed approximately two hours after intravenous administration of 100 MBq ⁹⁹ᵐTc-DMSA.

Imaging is acquired using a Siemens Symbia Intevo SPECT system equipped with low-energy high-resolution collimators.

Static anterior and posterior renal images are obtained to quantify split renal function using the geometric mean of tracer uptake.

Additional single-photon emission computed tomography (SPECT) imaging is performed to assess the presence and anatomical distribution of renal cortical defects consistent with scarring.

Scintigraphic findings are compared between kidneys and between study groups and evaluated in relation to regional MRI and ultrasound elastography findings.

Statistical Analysis

Statistical analyses will focus on intraindividual and between-group differences in renal structure and function.

Linear mixed-effects models (LMMs) will be used in the statistical analysis, accounting for the correlation between repeated regional measurements obtained from kidneys within the same participant.

The models will assess differences between the previously instrumented and contralateral kidneys in patients and compare imaging parameters between patients and healthy controls.

Regional findings from MRI, ultrasound elastography, and DMSA scintigraphy will be evaluated for anatomical correspondence.

The study is exploratory, with a limited sample size. Statistical findings will be interpreted with consideration of effect estimates, uncertainty, and the potential for confounding. Observed associations will not be considered evidence of causality.

Ethical Considerations

The study was approved by the Regional Committee on Health Research Ethics, Southern Denmark (approval number S-20240065).

All participants provide written informed consent before undergoing study-specific examinations.

MRI and ultrasound examinations are non-invasive, and MRI is performed without intravenous contrast administration. DMSA scintigraphy involves exposure to a low dose of ionising radiation.

Study data are handled in accordance with applicable data protection regulations.

The study is intended to provide preliminary clinical evidence regarding potential long-term renal structural and functional alterations following repeated ureteroscopic procedures and to inform the design of future investigations.