Association of kidney function and metabolic risk factors with density of glomeruli on renal biopsy samples from living donors

OBJECTIVE: To test the hypothesis that kidney function and metabolic risk factors are associated with glomerular density on renal biopsy samples from healthy adults.PATIENTS AND METHODS: This study compared glomerular density with predonation kidney function, blood pressure, and metabolic risk factors in living kidney donors at Mayo Clinic in Rochester, MN, from May 10, 1999, to February 4, 2009. During implantation of the kidney allograft, an 18-gauge core needle biopsy sample of the renal cortex was obtained, sectioned, and examined by pathologists. Glomerular density was determined by the number of glomeruli (normal and sclerotic) divided by area of cortex.RESULTS: The study sample of 1046 kidney donors had a mean of 21 glomeruli (0.8 sclerotic glomeruli) and a glomerular density of 2.3 glomeruli per square millimeter. In a subset of 54 donors, glomerular density inversely correlated with the mean glomerular area (r_s=−0.28). Independent predictors of decreased glomerular density were older age, increased glomerular filtration rate, family history of end-stage renal disease, increased serum uric acid, and increased body mass index. Increased urine albumin excretion, hypertension, decreased high-density lipoprotein cholesterol, and metabolic syndrome were also associated with decreased glomerular density after age-sex adjustment. These associations were not explained by the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, or arteriosclerosis on the renal biopsy sample. In older donors, decreased glomerular density was attenuated by an increased prevalence of glomerulosclerosis and tubular atrophy.CONCLUSION: Decreased glomerular density is associated with many different kidney function and metabolic risk factors among relatively healthy adults and may represent an early state of increased risk of parenchymal injury.BMI = body mass index; CKD = chronic kidney disease; ESRD = end-stage renal disease; GFR = glomerular filtration rate; HDL = high-density lipoproteinThe size of individual nephrons can reflect important elements of metabolic regulation. Persons with a low nephron endowment or with certain stress states (eg, obesity, pregnancy, or unilateral nephrectomy) develop glomerular hypertension and increased single-nephron filtration (hyperfilter) with compensatory glomerulomegaly.^1-5 Glomerulomegaly from hyperfiltration also occurs in response to nephron loss, perhaps due to a shift in perfusion from nonviable to viable nephrons.^6,7 In addition to glomerulomegaly, hyperfiltration leads to tubular hypertrophy and hyperplasia.^8-10 Much of the volume increase of viable nephrons in response to hyperfiltration may be in the proximal tubule rather than the glomerulus.^11-13 Unfortunately, there is no safe and practical method to directly measure the average volume occupied by nephrons in living humans.Normal kidney parenchyma consists only of nephrons and supporting vessels, with a trivial amount of interstitium (Figure 1), and thus glomerular density on sectioned biopsy samples of renal cortex is inversely proportional to average nephron size to some extent. We hypothesized that glomerular density is associated with kidney function and metabolic characteristics of the kidney. Specifically, among persons with risk factors for glomerular hypertension and hyperfiltration, the glomerular density would be decreased. The rationale for this hypothesis is that any process that increases the volume occupied by each nephron would effectively push glomeruli apart, leading to decreased glomerular density. For example, decreased glomerular density has been associated with low birth weight in neonates and, in this instance, has been attributed to low nephron endowment with compensatory hypertrophy.¹⁴ Alternatively, kidney function and metabolic risk factors may be associated with global glomerulosclerosis (complete scarring of glomerulus), and reabsorption of these sclerotic glomeruli¹⁵ could decrease glomerular density.Open in a separate windowFIGURE 1.Representative fields of implantation biopsies (original magnification x100; hematoxylin-eosin) for kidney donors with (top) high glomerular density (10 glomeruli in a representative field of a biopsy section) and (bottom) low glomerular density (2 glomeruli in a representative field of a biopsy section). G = glomerulus.For editorial comment, see page 271In the current study, we used adult living kidney donors with implantation (intraoperative) renal biopsy samples to study glomerular density. Although kidney donors are selected on the basis of good health, they still demonstrate substantial variation in kidney function,blood pressure, and metabolic profiles.¹⁶ Our goal was to compare glomerular density against predonation clinical characteristics, particularly those that have previously been implicated in glomerular hyperfiltration and glomerular hypertension or are risk factors for chronic kidney disease (CKD).