Urinary concentrating ability decreases with age in both humans and animals. This phenomenon is not yet clearly explained or corroborated by morphological findings, often focused on glomerular changes. In rats aged 5-22 months, semi-quantitative and quantitative morphometric analysis was performed to score cortical and medullary changes. Morphological-data were related to renal functional parameters. Three stages of tubulo-interstitial injury were observed: minimal findings (stage I); mild fibrosis with atrophy and casts in medullary thick ascending limbs (stage II): extensive fibrosis and atrophy with large cast formation (stage III). Maximal urinary osmolality decreased in correlation with the stage of tubulointerstitial injury (r = -0.8, P < 0.001), from 3735 mosmol L-1 at stage I to 2807 at stage II and 1567 at stage III. A dissociation was observed in the rate of progression with age between tubulointerstitial injury and glomerular sclerosis. Whereas sclerosis was observed in only 2-3% of glomeruli at both stages I and II of tubulointerstitial injury, damage to thick ascending limbs significantly increased from 2% of tubules at stage 1 to 11% at stage II (P < 0.002). At stage III, both extensive glomerular sclerosis (53%) and tubular injury (32%) were present. Uninephrectomy accelerated both morphological injury and functional compromise. We conclude that, in the early stages of renal ageing, injury to medullary tubules may be more prevalent than injury to glomeruli and could be responsible for the reduction in concentrating ability.