Progressive Nephron Loss in Aging Kidneys: Clinical-Structural Associations Investigated by Two Anatomical Methods

Abstract

Two major studies of structural changes associated with aging in human kidneys are reviewed and new information presented. The studies are the Monash University stereologically analyzed series of 319 autopsy kidneys from the United States in which 44% were white and the Mayo Clinic CT angiogram/biopsy analysis of 1,388 US kidney donors in which 97% were white. Hypertension rates in the Monash series were 48% and included moderate and severe hypertension. In the Mayo Clinic study, 12% had mild hypertension. The studies showed no relationship between glomerular number and hypertension except for a weak relationship with older white women in the Monash series. An inverse relationship was present between glomerular number and glomerular volume, a reciprocity that tended to enhance glomerular mass and by inference filtration capacity with lower nephron numbers. This relationship seemed to be present whether low nephron numbers were intrinsic or acquired. In the Mayo Clinic studies, pretransplant iothalamate clearances demonstrated that single nephron (SN) glomerular filtration rates (GFR) were similar throughout the range of glomerular number in subjects younger than 70 years, but that increased SNGFR correlated with nephron hypertrophy and increased nephrosclerosis particularly at 70 years of age and over. Hypertension at least through middle age cannot be related to a deficiency of glomeruli, but glomeruli are lost with later aging in association with adaptive nephron hypertrophy that can maintain GFR near normal. These studies help define an age-related nephropathy that overlaps with hypertension as a potential cause of end-stage renal disease when glomerulosclerosis is advanced.

Keywords: aging; birth weight; glomerulosclerosis; nephrosclerosis; stereology.

Figure 1

(A). The physical disector apparatus used to estimate glomerular number in the Monash series. This consists of tandem microscopes projecting images of a pair of histologic sections from tissue blocks representing a known fraction of the kidney cortex. (B). Identical areas of the paired sections are projected side by side. On the right is the “reference” section with an unbiased counting frame that analyzes glomeruli not touching the forbidden (dark) lines. The “look‐up” section is on the left. A glomerulus present in the unbiased counting frame but not in the look‐up section is counted

Figure 2

Enhanced CT and renal biopsy. (A). CT of a kidney with the cortex outlined in white. Serial reconstruction then allows an estimate of total cortical volume. (B). A renal biopsy 8.0 × 1.8 mm contains six glomeruli for a glomerular density of 0.42/mm². Mean glomerular area for the biopsy is measured, and volume and density are estimated in three dimensions by Weibel and Gomez formulae (1962)

Figure 3

From the Monash series study of the US adults (≥18 years old). Significant direct relationships were found between birth weight and glomerular number (A), birth weight and adult height (B), and adult height and glomerular number (C). There is a strong inverse relationship between total glomerular number and mean glomerular volume in which lower numbers of glomeruli predict larger glomerular size (D). The product of total glomerular number and mean glomerular volume represents total glomerular volume (V_glomtotal), an estimate of the filtration capacity of the kidney. V_glomtotal increases with height (E) in a manner that somewhat attenuates the glomerular number/glomerular volume relationship but still indicates that prenatal kidney development attempts to achieve a filtration capacity needed for a predetermined adult body size. In the figures, r denotes Pearson linear regression