An Improved Method for Estimating Nephron Number and the Association of Resulting Nephron Number Estimates with Chronic Kidney Disease Outcomes

Abstract

Significance Statement Nephron number currently can be estimated only from glomerular density on a kidney biopsy combined with cortical volume from kidney imaging. Because of measurement biases, refinement of this approach and validation across different patient populations have been needed. The prognostic importance of nephron number also has been unclear. The authors present an improved method of estimating nephron number that corrects for several biases, resulting in a 27% higher nephron number estimate for donor kidneys compared with a prior method. After accounting for comorbidities, the new nephron number estimate does not differ between kidney donors and kidney patients with tumor and shows consistent associations with clinical characteristics across these two populations. The findings also indicate that low nephron number predicts CKD independent of biopsy and clinical characteristics in both populations. Background Nephron number can be estimated from glomerular density and cortical volume. However, because of measurement biases, this approach needs refinement, comparison between disparate populations, and evaluation as a predictor of CKD outcomes. Methods We studied 3020 living kidney donors and 1354 patients who underwent radical nephrectomy for tumor. We determined cortex volume of the retained kidney from presurgical imaging and glomerular density by morphometric analysis of needle core biopsy of the donated kidney and wedge sections of the removed kidney. Glomerular density was corrected for missing glomerular tufts, absence of the kidney capsule, and then tissue shrinkage on the basis of analysis of 30 autopsy kidneys. We used logistic regression (in donors) and Cox proportional hazard models (in patients with tumor) to assess the risk of CKD outcomes associated with nephron number. Results Donors had 1.17 million nephrons per kidney; patients with tumor had 0.99 million nephrons per kidney. A lower nephron number was associated with older age, female sex, shorter height, hypertension, family history of ESKD, lower GFR, and proteinuria. After adjusting for these characteristics, nephron number did not differ between donors and patients with tumor. Low nephron number (defined by <5th or <10th percentile by age and sex in a healthy subset) in both populations predicted future risk of CKD outcomes independent of biopsy and clinical characteristics. Conclusions Compared with an older method for estimating nephron number, a new method that addresses several sources of bias results in nephron number estimates that are 27% higher in donors and 1% higher in patients with tumor and shows consistency between two populations. Low nephron number independently predicts CKD in both populations.

The Number and Size of Individual Kidney Medullary Pyramids is Associated with Clinical Characteristics, Kidney Biopsy Findings, and CKD Outcomes among Kidney Donors

“…Then, using Weibel and Gomez stereology models, we calculated the mean nonsclerosed glomerular tuft volume (using only traced tufts) and volumetric nonsclerosed glomerular density (using both traced and missing tufts). 22 Cortex per nonsclerosed glomerulus, a measure of nephron size, was then calculated as the inverse of the volumetric nonsclerosed glomerular density. On TRI-stained sections, we manually traced the cortex, each globally sclerosed glomerulus, distinct IFTA foci, 23 luminal boundary, and intimal-media boundary of the most orthogonal artery (if artery present).…”

“…7 Nephron number was calculated by multiplying the glomerular density and cortex volume obtained by semiautomated segmentation using ITK-SNAP software (version 2.2; University of Pennsylvania, Philadelphia, PA). 22…”

Morphometric analysis of chronicity on kidney biopsy: a useful prognostic exercise

“…Several studies have utilized morphometry evaluation of both kidney biopsy images and computed tomography or magnetic resonance kidney images to calculate the nephron number from the density of glomeruli in the cortex multiplied with the total volume of cortex per kidney [ 13–17 ]. Low nephron number predicts adverse kidney function outcomes in both living kidney donors and tumor patients [ 16 , 18 ]. Nephron number and nephron size have a reciprocal relationship due to compensatory enlargement of nephrons with low nephron endowment or nephron loss due to aging and disease.…”

“…There is evidence that enlarged nephrons and low nephron number are associated with a worse kidney prognosis in a variety of patient populations. Larger glomerular volume and low nephron number predicted a low GFR early and long-term after kidney donation and graft failure in the recipient [ 16 , 18 , 33 , 34 ]. Larger glomerular volume predict outcomes as progressive CKD in several studies with different population [ 3 , 5 , 35 ].…”

“…Glomerular counts can be reported per section or as total count across serial sections, but undercounting of glomeruli by visual inspection alone is a common problem. A morphometric approach ensures standardized counting of glomeruli and inclusion of partial counts for glomeruli bisected by the biopsy needle [ 16 ]. Global glomerulosclerosis is evident in both aging and in kidney disease.…”