MRI-based glomerular morphology and pathology in whole human kidneys

Abstract

Nephron number (N(glom)) and size (V(glom)) are correlated with risk for chronic cardiovascular and kidney disease and may be predictive of renal allograft viability. Unfortunately, there are no techniques to assess N(glom) and V(glom) in intact kidneys. This work demonstrates the use of cationized ferritin (CF) as a magnetic resonance imaging (MRI) contrast agent to measure N(glom) and V(glom) in viable human kidneys donated to science. The kidneys were obtained from patients with varying levels of cardiovascular and renal disease. CF was intravenously injected into three viable human kidneys. A fourth control kidney was perfused with saline. After fixation, immunofluorescence and electron microscopy confirmed binding of CF to the glomerulus. The intact kidneys were imaged with three-dimensional MRI and CF-labeled glomeruli appeared as punctate spots. Custom software identified, counted, and measured the apparent volumes of CF-labeled glomeruli, with an ~6% false positive rate. These measurements were comparable to stereological estimates. The MRI-based technique yielded a novel whole kidney distribution of glomerular volumes. Histopathology demonstrated that the distribution of CF-labeled glomeruli may be predictive of glomerular and vascular disease. Variations in CF distribution were quantified using image texture analyses, which be a useful marker of glomerular sclerosis. This is the first report of direct measurement of glomerular number and volume in intact human kidneys.

Architecture of the human renal inner medulla and functional implications

“…These whole organs experienced virtually no warm ischemia (0 -60 min) and minimal cold ischemia (12-24 h) and were shipped in preservation solution directly from the operating room recovery suite, received within 24 h, and immediately dissected and fixed as described below. Anatomic studies with kidneys sourced from IIAM include Beeman et al (4). Observations from our initial studies with kidneys from IIAM were fully replicated in tissue obtained from the Beth Israel Medical Center.…”

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

“…Therefore, glomerular volume has also been proposed as a surrogate marker for reduced nephron numbers in the absence of other causes. A promising innovative method for nephron enumeration is the use of cationic ferritin as an MRI-detectable contrast agent, which highlights the glomerular basement membrane of each nephron [71,72,73,74]. This contrast allows for the quantification of all glomeruli in a nondestructive manner and may potentially be useful in vivo.…”

Can Renal Biopsy Be Used to Estimate Total Nephron Number?

“…Noninvasive imaging techniques have failed, even with the best soft tissue resolution and highfield strength magnetic resonance, because the glomeruli cannot be differentiated from the other compartments in the kidney. To address this problem, investigators have been exploring a contrast agent, cationic ferritin (CF), developed to discriminate the glomeruli that are perfused from surrounding tubules and vasculature (24,25). When systemically administered to animals or directly injected to the renal artery of an ex vivo human kidney deemed unsuitable for transplant, the CF transiently binds to the glomerular basement membrane.…”

“…This method allows for a comprehensive view of the kidney and avoids the biases and estimations inherent in renal biopsy data. Groups have shown how CF-enhanced MRI can be used to enumerate nephron number in living rodents (24,25). This noninvasive method to count and measure the size of glomeruli on a repeatable basis has the potential to transform our understanding of the variability of nephron number and progression of renal disease in LBW infants.…”