Nephron loss detected by MRI following neonatal acute kidney injury in rabbits

Abstract

Background: Acute kidney injury affects nearly 30% of preterm neonates in the intensive care unit. We aimed to determine if nephrotoxin-induced AKI disrupted renal development assessed by imaging (CFE-MRI). Methods: Neonatal New Zealand rabbits received indomethacin and gentamicin (AKI) or saline (control) for four days followed by cationic ferritin (CF) at six weeks. Ex vivo images were acquired using a gradient echo pulse sequence on 7T MRI. Glomerular number (N glom) and apparent glomerular volume (aV glom) were determined. CF toxicity was assessed at 2 and 28 days in healthy rabbits. Results: N glom was lower in the AKI group as compared to controls (74,034 vs 198,722, p<0.01). aV glom was not different (AKI:7.3 ×10 −4 vs. control: 6.2 ×10 −4 mm 3 , p=0.69). AKI kidneys had a band of glomeruli distributed radially in the cortex that were undetectable by MRI. Following CF injection, there was no difference in body or organ weights except for the liver, and transient changes in serum iron, platelets and white blood cell count. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Mapping vascular and glomerular pathology in a rabbit model of neonatal acute kidney injury using MRI

“…In this work, we have examined the development of vascular and glomerular pathology in a rabbit model of neonatal AKI, using 3D MRI. Although, indomethacin and gentamicin have been established as nephrotoxic in the developing kidney of the neonatal rabbit (Charlton et al, 2019), to our knowledge no studies have examined the long-term effect of the combination of these drugs on the vasculature integrated with glomerular morphology of the whole kidney. We have demonstrated that a short exposure to commonly encountered medications during an active period of nephrogenesis results in a 50% reduction of glomeruli by MRI, along with significant vascular changes, with differences in the spatial maps of the cortical vasculature and the glomeruli.…”

“…We developed the model of renal injury in neonatal rabbits using indomethacin and gentamicin and the biochemical and histologic evaluation of this model was recently published (Charlton et al, 2019). Gentamicin and indomethacin are medications used clinically in preterm human neonates to treat deadly bacterial infections and patent ductus arteriosus, but are associated with neonatal AKI (Rhone et al, 2014).…”

“…Ninety minutes after the injection of CF, rabbits received ketamine (80 mg/kg) and xylazine (10 mg/kg) IP, followed by isofluorane for transcardiac perfusion. The left renal artery was clamped to avoid formalin fixation (this tissue was examined by transmission electron microscopy in a previously published study (Charlton et al, 2019)). Physiological saline and then 10% buffered formalin phosphate were infused into the right kidney.…”

Glomerular developmental delay and proteinuria in the preterm neonatal rabbit

“…Also, in the current setting we were not able to perform the experiment using cationic ferritin enhanced-MRI, a novel and promising tool to quantify perfused glomeruli. This method, however, would not provide insight into differences in the developmental stages of the glomeruli that were found [ 30 , 31 ]. Secondarily, kidneys were embedded in paraffin: a method known to cause 40–50% shrinkage of soft tissues such as the kidney [ 32 ].…”

New imaging tools to measure nephron number in vivo: opportunities for developmental nephrology

“…31 More recently, we showed that acute kidney injury in a neonatal rabbit model caused a detectable loss of glomeruli with vascular reorganization. 35 Thus, tracking changes in CF labeling by MRI may be an important tool to understand the impact of damage during development and its impact of renal health later in life.…”