The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging

Abstract

Nephron number may be an important determinant of kidney health but has been difficult to study in living humans. We evaluated 1638 living kidney donors at Mayo Clinic (MN and AZ sites) and Cleveland Clinic. We obtained cortical volumes of both kidneys from predonation computed tomography scans. At the time of kidney transplant, we obtained and analyzed the sections of a biopsy specimen of the cortex to determine the density of both nonsclerotic and globally sclerotic glomeruli; the total number of glomeruli was estimated from cortical volume×glomerular density. Donors 18-29 years old had a mean 990,661 nonsclerotic glomeruli and 16,614 globally sclerotic glomeruli per kidney, which progressively decreased to 520,410 nonsclerotic glomeruli per kidney and increased to 141,714 globally sclerotic glomeruli per kidney in donors 70-75 years old. Between the youngest and oldest age groups, the number of nonsclerotic glomeruli decreased by 48%, whereas cortical volume decreased by only 16% and the proportion of globally sclerotic glomeruli on biopsy increased by only 15%. Clinical characteristics that independently associated with fewer nonsclerotic glomeruli were older age, shorter height, family history of ESRD, higher serum uric acid level, and lower measured GFR. The incomplete representation of nephron loss with aging by either increased glomerulosclerosis or by cortical volume decline is consistent with atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons. In conclusion, lower nephron number in healthy adults associates with characteristics reflective of both lower nephron endowment at birth and subsequent loss of nephrons.

Keywords: Aging; Nephron loss; Nephron number; kidney.

Figure 1.

Selection of study sample.

Figure 2.

Nephron number and GFR progressively decrease even with healthy aging. The mean number of NSG and GSG per kidney are shown by age group (left y-axis). The mean GFR for each age group is shown by the connected black circles (right y-axis). GFR decline is proportional to the decline in NSG with aging except in the oldest age group. However, potential donors with a GFR<65 ml/min per 1.73 m² are excluded from donation which disproportionately impacts the oldest age group.

Figure 3.

Nephron number has a reciprocal relationship with nephron size. Nephron size was measured by (A) nonsclerotic glomerular volume and (B) profile tubular area. The curve is a reciprocal regression fit.

Figure 4.

Kidney function and risk factors relate to loss of nephrons. Congenital risk factors lead to lower nephron endowment (fewer NSG) at birth. With aging, hypertension, ischemia, CKD, or AKI there is loss of nephrons to glomerulosclerosis with eventual reabsorption of the GSG. This loss of nephrons is detectable to some extent by lower GFR and higher uric acid levels. There is also evidence of compensatory hypertrophy of the remaining nephrons.