Age-Based Versus Young-Adult Thresholds for Nephrosclerosis on Kidney Biopsy and Prognostic Implications for CKD

Abstract

Significance statement: Nephrosclerosis (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) is the defining pathology of both kidney aging and CKD. Optimal thresholds for nephrosclerosis that identify persons with a progressive disease are unknown. This study determined a young-age threshold (18-29 years) and age-based 95th percentile thresholds for nephrosclerosis on the basis of morphometry of kidney biopsy sections from normotensive living kidney donors. These thresholds were 7.1-fold to 36-fold higher in older (70 years or older) versus younger (aged 18-29 years) normotensive donors. Age-based thresholds, but not young-age threshold, were prognostic for determining risk of progressive CKD among patients who underwent a radical nephrectomy or a for-cause native kidney biopsy, suggesting that age-based thresholds are more useful than a single young-age threshold for identifying CKD on biopsy.

Background: Nephrosclerosis, defined by globally sclerotic glomeruli (GSG) and interstitial fibrosis and tubular atrophy (IFTA), is a pathology of both kidney aging and CKD. A comparison of risk of progressive CKD using aged-based thresholds for nephrosclerosis versus a single young-adult threshold is needed.

Methods: We conducted morphometric analyses of kidney biopsy images for %GSG, %IFTA, and IFTA foci density among 3020 living kidney donors, 1363 patients with kidney tumor, and 314 patients with native kidney disease. Using normotensive donors, we defined young-age thresholds (18-29 years) and age-based (roughly by decade) 95th percentile thresholds. We compared age-adjusted risk of progressive CKD (kidney failure or 40% decline in eGFR) between nephrosclerosis that was "normal compared with young," "normal for age but abnormal compared with young," and "abnormal for age" in patients with tumor and patients with kidney disease.

Results: The 95th percentiles in the youngest group (18-29 years) to the oldest group (70 years or older) ranged from 1.7% to 16% for %GSG, 0.18% to 6.5% for %IFTA, and 8.2 to 59.3 per cm 2 for IFTA foci density. Risk of progressive CKD did not differ between persons with nephrosclerosis "normal compared with young" versus "normal for age but abnormal compared with young." Risk of progressive CKD was significantly higher with %GSG, %IFTA, or IFTA foci density that was abnormal versus normal for age in both cohorts.

Conclusions: Given that increased risk of progressive CKD occurs only when nephrosclerosis is abnormal for age, age-based thresholds for nephrosclerosis seem to be better than a single young-age threshold for identifying clinically relevant CKD.

Figure 1

Representative biopsy images. Images show increasing severity of nephrosclerosis from (A) low-risk living kidney donors to (B) medium-risk patients with kidney tumor to (C) high-risk patients with native kidney disease. For each image, the cortex is traced in green; non–globally sclerosed glomeruli are traced in blue; globally sclerosed glomeruli are traced in red; and each distinct IFTA foci are traced in black. GSG, globally sclerotic glomeruli; IFTA, interstitial fibrosis and tubular atrophy.

Figure 2

Conceptual model of young- and age-based thresholds for nephrosclerosis measures defined using normotensive kidney donors. The 95th percentile for 18–29 years defines the abnormal compared with young threshold. The 95th percentile for 70–77 years defines the abnormal for age threshold for all persons 70 years and older. Using these thresholds, patients can be grouped into normal compared with young, normal for age but abnormal compared with young, and abnormal for age.

Figure 3

Thresholds for nephrosclerosis in normotensive living kidney donors based on the 95th percentile for young (18–29 years) and the 95th percentile for each age group. For (A) %GSG, (B) %IFTA, and (C) IFTA foci density, the abnormal compared with young threshold were 1.7%, 0.18%, and 8.2 per cm², whereas the abnormal for age threshold ranged from 1.7% to 16%, 0.18%–5.6%, and 8.2–59.3 per cm², respectively. GSG, globally sclerotic glomeruli; IFTA, interstitial fibrosis and tubular atrophy.

Figure 4

Risk of progressive CKD. The risk of kidney failure or a 40% decline in eGFR in patients with kidney tumor (A–C) and patients with kidney disease (D–F) by nephrosclerosis measures (%GSG, %IFTA, and IFTA foci density) normal for age versus abnormal for age. GSG, globally sclerotic glomeruli; IFTA, interstitial fibrosis and tubular atrophy.