Mapping nephron mass in vivo using positron emission tomography

Abstract

Nephron number varies widely in humans. A low nephron endowment at birth or a loss of functioning nephrons is strongly linked to increased susceptibility to chronic kidney disease. In this work, we developed a contrast agent, radiolabeled cationic ferritin (RadioCF), to map functioning glomeruli in vivo in the kidney using positron emission tomography (PET). PET radiotracers can be detected in trace doses (<30 nmol), making them useful for rapid clinical translation. RadioCF is formed from cationic ferritin (CF) and with a radioisotope, Cu-64, incorporated into the ferritin core. We showed that RadioCF binds specifically to kidney glomeruli after intravenous injection in mice, whereas radiolabeled noncationic ferritin (RadioNF) and free Cu-64 do not. We then showed that RadioCF-PET can distinguish kidneys in healthy wild-type (WT) mice from kidneys in mice with oligosyndactylism (Os/+), a model of congenital hypoplasia and low nephron mass. The average standardized uptake value (SUV) measured by PET 90 min after injection was 21% higher in WT mice than in Os/+ mice, consistent with the higher glomerular density in WT mice. The difference in peak SUV from SUV at 90 min correlated with glomerular density in male mice from both WT and Os/+ cohorts ( R2 = 0.98). Finally, we used RadioCF-PET to map functioning glomeruli in a donated human kidney. SUV within the kidney correlated with glomerular number ( R2= 0.78) measured by CF-enhanced magnetic resonance imaging in the same locations. This work suggests that RadioCF-PET appears to accurately detect nephron mass and has the potential for clinical translation.

Novel strategies in nephrology: what to expect from the future?

“…The accumulation of ferritin in the glomeruli allows its detection, mapping of the entire kidney in vivo and co-localization of glomeruli with other structures such as the microvasculature. To support the use of nephron number as a clinical parameter, the cationized ferritin molecule of CFE-MRI has been modified to form radiolabeled cationic ferritin (RadioCF), a radiotracer used in positron emission tomography (PET) to map functioning glomeruli in vivo in the kidney [ 19 ]. RadioCF-PET accurately quantifies nephron mass in animals and had the potential for clinical translation [ 19 ].…”

“…To support the use of nephron number as a clinical parameter, the cationized ferritin molecule of CFE-MRI has been modified to form radiolabeled cationic ferritin (RadioCF), a radiotracer used in positron emission tomography (PET) to map functioning glomeruli in vivo in the kidney [ 19 ]. RadioCF-PET accurately quantifies nephron mass in animals and had the potential for clinical translation [ 19 ]. Radio-CF is formed by integration of a radioisotope, Cu-64, to the cationic ferritin (CF) and has been shown to bind functional glomeruli when given intravenously [ 19 ].…”

“…RadioCF-PET accurately quantifies nephron mass in animals and had the potential for clinical translation [ 19 ]. Radio-CF is formed by integration of a radioisotope, Cu-64, to the cationic ferritin (CF) and has been shown to bind functional glomeruli when given intravenously [ 19 ]. RadioCF-PET can map and measure the areas of functional nephron loss making it a diagnostic tool that can also predict CKD progression [ 14 ].…”

The utilization of positron emission tomography in the evaluation of renal health and disease

“…GFR has been quantitated in n = 1 study with 68 Ga-EDTA [53], while 11 C-PABA has been shown to be safe in humans and could be used for functional renal imaging [54]. In a study by Baldelomar et al [55], a mouse model was used to map nephron mass as proof of concept in a donated human kidney in vivo with RadioCF [55]. Higher renal artery F-Na-F uptake has also been associated with higher cardiovascular risk and lower GFR [56].…”

“…The most utilized PET radiotracers were 15 O-labeled radio water (H 2 15 O, n = 14) and 18 F-fluorodeoxyglucose ( 18 F-FDG, n = 8). Other radiotracers used in at least one study were 14(R,S)-( 18)F-fluoro-6-thia-heptadecanoic acid ( 18 F-FTHA), 18 F-Sodium Fluoride ( 18 F-NaF), 11 C-acetate, 68-Gallium ( 68 Ga), 13 N-ammonia ( 13 N-NH 3 ), Rubidium-82 ( 82 Rb), radiolabeled cationic ferritin (RadioCF), 11 C-para-aminobenzoic acid ( 11 C-PABA), Gallium-68 pentixafor ( 68 Ga-Pentixafor), 2-deoxy-2-F-fluorod-sorbitol (F-FDS) and 55 Co-ethylene diamine tetra acetic acid ( 55 Co-EDTA). Conclusion PET imaging provides an effective modality for evaluating a range of metabolic functions including glucose and fatty acid uptake, oxygen consumption and renal perfusion.…”