Estimating Nephron Number from Biopsies: Impact on Clinical Studies

Abstract

Background: Accumulating evidence supports an association between nephron number and susceptibility to kidney disease. However, it is not currently possible to directly measure nephron number in a clinical setting. Recent clinical studies have used glomerular density from a single biopsy and whole kidney cortical volume from imaging to estimate both nephron number and single nephron glomerular filtration rate. However, the accuracy of these estimates from individual subjects is unknown. Furthermore, it is not clear how sample size or biopsy location may influence these estimates. These questions are critical to study design and to the potential translation of these tools to estimate nephron number in individual subjects. Methods: We measured the variability in estimated nephron number derived from needle or virtual biopsies and cortical volume in human kidneys declined for transplantation. We performed multiple needle biopsies in the same kidney, and examined the three-dimensional spatial distribution of nephron density by magnetic resonance imaging. We determined the accuracy of a single kidney biopsy to predict the mean nephron number estimated from multiple biopsies from the same kidney. Results: A single needle biopsy had a 15% chance and virtual biopsy had a 60% chance of being within 20% of whole kidney nephron number. Single needle biopsies could be used to detect differences in nephron number between large cohorts of several hundred subjects. Conclusions: The number of subjects required to accurately detect differences in nephron number between populations can be predicted based on natural intra-kidney variability in glomerular density. A single biopsy is insufficient to accurately predict nephron number in individual subjects.

Prediction of Renal Function in Living Kidney Donors and Recipients of Living Donor Kidneys Using Quantitative Histology

“…32 This could reflect cortex volume as a better indicator of true glomerular number and the uncertainty related to determining total glomerular number based on 1 or 2 biopsies. 33 However, it may also be explained by the complex physiological regulation of GFR being influenced by functional parameters as glomerular pressure and hydraulic permeability not measurable by quantitative histology.…”

“…An important limitation is the relative limited sample size that refrained us from demonstrating weak associations or to include more variables in the regression analysis. Estimation of glomerular number based on limited tissue material, and in addition algorithms that differ between labs, is associated with uncertainty, 33 possibly rendering glomerular quantitative histology more uncertain than determination of interstitial fibrosis.…”

Renal MRI: From Nephron to NMR Signal

“…174 This is a major leap since there is no preferred sampling location for biopsy and as many as 200 core needle biopsies would be needed to estimate kidney nephron number within 20% of the ground truth nephron number measured by cationicferritin enhanced MRI, with 95% confidence. 175 While cationic ferritin MRI quantification of nephron number remains an ex vivo and preclinical application, radiolabed cationic ferritin makes in vivo nephron number quantification with PET (-MRI) a possibility in humans. 176 As previously mentioned, kidney macrophage infiltration, in addition to reduction in nephron number, portends poor prognosis in several kidney diseases.…”

“…Bennet and coworkers developed a method of measuring nephron number by cationic‐ferritin‐enhanced MRI in vivo in animals and in ex vivo human kidneys 174 . This is a major leap since there is no preferred sampling location for biopsy and as many as 200 core needle biopsies would be needed to estimate kidney nephron number within 20% of the ground truth nephron number measured by cationic‐ferritin enhanced MRI, with 95% confidence 175 . While cationic ferritin MRI quantification of nephron number remains an ex vivo and preclinical application, radiolabed cationic ferritin makes in vivo nephron number quantification with PET(‐MRI) a possibility in humans 176 …”

Healthy and unhealthy aging on kidney structure and function: human studies

“…Over a >50-year span of aging about 50% of the original nephron endowment is lost by physiological aging [20,21]. Although enumerating nephrons by combinations of volumetric CT scans for cortical volume and kidney biopsy stereology for glomerular density is not precise in individual patients [22 ▪ ], reasonably accurate population-level patterns can be described in large cohorts [20,23–25]. Another interesting aspect of age-related global glomerulosclerosis is that it increases with age primarily in the superficial cortex (Figs.…”