Authors’ Reply

• nephron
• renal morphology
• glomerulus

We thank Seibel and colleagues¹ for their thoughtful letter on the importance of nephron number. We agree that nephron number warrants investigation as a prognostic marker in the kidney cancer population.

However, we would also argue that glomerular density should not be simply viewed as a surrogate for nephron number. Certainly, this is true to some extent, as nephron number is estimated from glomerular density (calculated with stereology applied to kidney biopsy section) multiplied by cortical volume. However, we would restate this relationship in a different manner. Cortical volume can be estimated from average nephron size in the cortex (cortex per glomerulus or the reciprocal of glomerular density) multiplied by nephron number.² The interpretation of cortex per glomerulus as a measure of average nephron size is supported by its correlation with glomerular volume (r_s=0.83, P<0.001) and with mean cross-sectional tubular area (r_s=0.66, P<0.001) in our study.³ A concern with interpreting cortex per glomerulus as nephron size may be that some of the volume occupied by the cortex is not functioning nephrons but rather, interstitial fibrosis/tubular atrophy (IF/TA). However, even after excluding regions of IF/TA, the correlation of nonfibrotic cortex per glomerulus with glomerular volume (r_s=0.84, P<0.001) and cross-sectional tubular area (r_s=0.66, P<0.001) were not meaningfully different nor was the prediction of CKD progression.³

We argue that cortex per glomerulus, glomerular volume, and tubular cross-sectional area are all measures of nephron size, but there are also important differences and limitations with each. Glomerular volume does not capture the volume occupied by tubules, and only about 4% of the cortical volume is due to volume from glomeruli.² Some clinical factors, such as aging, appear to be associated with an increase in the size of tubules but not the size of glomeruli.⁴ The cross-sectional tubular area does not account for the different orientations, differing segments, and/or differing lengths of the tubules. Cortex per glomerulus may better account for the three-dimensional volume occupied by tubules in the cortex, but it does not exclude the volume occupied by vessels and IF/TA. None of these measures account for the volume occupied by nephron in the medulla. However, studying all three of these measures together may provide a more complete picture of nephron size than any alone.

Clinical characteristics can associate differently with nephron size and nephron number. In a relatively heathy population, obesity associates with larger nephrons but not with nephron number; lower GFR is not associated with nephron size but associates with lower nephron number, and family history of ESKD associates with both larger and fewer nephrons.² Both nephron number and nephron size are important to study for the prediction of outcomes. Indeed, we recently found that both low nephron number for age and larger glomerular volume in donors predicted a GFR<45 ml/min per 1.73 m² a decade after kidney donation.⁵

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