Senile Nephrosclerosis – Does It Explain the Decline in Glomerular Filtration Rate with Aging?

Nephrosclerosis can be defined by the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis on renal biopsy. Chronic kidney disease is identified clinically by a reduction in glomerular filtration rate (GFR) and has been characterized histologically by nephrosclerosis. Many relatively healthy older adults have been diagnosed with chronic kidney disease because of a decline in GFR with normal aging. Recent data show that in healthy adults (living kidney donors), nephrosclerosis on renal biopsy does not associate with GFR independent of age. This may be explained by the decline in GFR and nephrosclerosis being universal with aging (i.e. senescence), by structural changes in the kidney other than nephrosclerosis impacting GFR, or by extrarenal factors affecting GFR decline with age. However, the argument that the age-related decline in GFR can be fully explained by the development of nephrosclerosis in a subset of older adults is not supported by existing data. Copyright © 2011 S. Karger AG, Basel Published online: August 10, 2011 Andrew D. Rule Mayo Clinic, 200 1st Street SW Rochester, MN 55905 (USA) Tel. +1 507 266 1045, E-Mail rule.andrew @ mayo.edu © 2011 S. Karger AG, Basel Accessible online at: www.karger.com/nep D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 7 :0 8: 59 P M Senile Nephrosclerosis – Does It Explain the Decline in GFR with Aging? Nephron Physiol 2011;119(suppl 1):p6–p11 p7 never undergo a renal biopsy. The rate of renal biopsy in the general population is approximately 2 per 10,000 person-years and is limited to a select group of patients [4, 5] . Thus, the underlying renal parenchymal characteristics for most with presumed CKD in the general population (13% of adults) [2] is unclear, creating uncertainty with systematically considering all GFR decline as kidney disease. The morphologic changes seen in the aging kidney can be described as nephrosclerosis, a term that often refers to parenchymal changes with hypertension. The classic textbook, Robbins and Cotran Pathological Basis of Disease, distinguishes ‘benign’ from ‘malignant’ nephrosclerosis, with the latter characterized by onion-skinning of arteries secondary to accelerated hypertension. Benign nephrosclerosis is described as ‘the renal pathology associated with sclerosis of renal arterioles and small arteries. The resultant effect is focal ischemia of parenchyma supplied by vessels with thickened walls and consequent narrowed lumens. The parenchymal effects include glomerulosclerosis and chronic tubulointerstitial injury, producing a reduction in functional renal mass’ [6] . However, there is uncertainty as to whether luminal narrowing from arteriosclerosis is actually causal for glomerulosclerosis or whether other undefined factors lead to both [7] . Systematic study of nephrosclerosis has been difficult as the entity is often tied to hypertension even though the same histological findings occur in normotensive older adults [8–10] . Moreover, nephrosclerosis in the aging kidney is not necessarily related only to blood pressure and vascular disease. Nephrosclerosis can be identified in kidneys by several different methods: gross appearance of a leathery granular kidney surface at autopsy, reduced kidney volume on an imaging study, or histologic findings from a cortical renal biopsy. On renal histology, glomerulosclerosis, tubular atrophy, interstitial fibrosis and arteriosclerosis often occur together, and become more common with aging ( fig. 1 , 2 ) [7, 10] . An operational definition for nephrosclerosis is the presence of two or more of these chronic histological abnormalities on a sectioned standard needle core biopsy [10] . These microanatomical changes of tubular atrophy and glomerulosclerosis with aging may account for the macroanatomical reduction in kidney size by 10% per decade of age seen on the computed tomographic scans of adults ( fig. 3 ) [11] . Global glomerulosclerosis with aging may seem particularly relevant to the decline in GFR with aging. After all, GFR is the sum of the single-nephron GFRs for all functioning glomeruli, which would exclude globally sclerosed glomeruli. The process leading to global glomerulosclerosis as a result of vascular compromise is not fully understood. Affected glomeruli develop increased basement membrane thickening and wrinkling and there is shrinkage of the glomerular tuft towards the vascular pole on light microscopy, along with periglomerular fibrosis [12] . There is eventual global sclerosis of the glomerular tuft with collagen deposition that fills Bowman’s space [9] . There may be eventual absorption of these sclerosed glomeruli since the total number of glomeruli in the kidney decreases with older age [13] . Alternatively, sclerotic glomeruli may be under-represented on sections due to their 18–29 Sc le ro si s sc or e