An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients

Background. Interstitial expansion is important in the progression of a variety of kidney diseases, including diabetic nephropathy (DN). However, the interstitial elements that constitute interstitial expansion in DN are unknown and are the subject of this report. Methods. Interstitial composition was analyzed in 15 longstanding type 1 diabetic patients, 8 with mild (≈1.5 × normal) and 7 with moderate (≈2 × normal) increases in cortical interstitial fractional volume [Vv(Int/cortex]. The mild group was 29 ± 5 (mean ± SD) years old with diabetes duration of 17 ± 5 years. The moderate group was older (41 ± 7 years; P < 0.03), had longer diabetes duration (28 ± 7 years; P = 0.002), lower creatinine clearance (90 ± 14 mL/min/1.73 m₂ vs. 109 ± 18 mL/min/1.73 m₂; P = 0.05) and used antihypertensive medications more frequently (0/8 vs. 4/7; P < 0.03) compared to the mild group. Age- and gender-matched normal controls (N = 9) also were studied. Interstitial composition was evaluated by morphometric analysis of electron microscopic (EM) micrographs systematically obtained without bias at high (×7500) and low (×1500) magnification. Results. Mild interstitial expansion was associated with an ≈50% increase in fractional volume of interstitial cells (P < 0.001) and ≈70% increase in fractional volume of interstitial nuclei (P < 0.01). Numerical density of interstitial nuclei was normal in these patients, suggesting that the interstitial cells might be larger rather than simply more numerous. An increase over normal in the interstitial fractional volume of fibrillary collagen of ≈50% was seen only with moderate expansion (P < 0.001), when creatinine clearance was already decreased. Interstitial expansion was associated with a decrease in volume and surface of peritubular capillaries as well as with a reduction in surface ratio of capillaries to tubules. Conclusions. In contrast to early mesangial expansion where matrix accumulation plays a dominant role, mild interstitial expansion in long-standing type 1 diabetic patients is largely due to an increase in the cell component of the interstitium. Increased fractional volume of interstitial fibrillary collagen is only seen at later stages of the disease, when the glomerular filtration rate is already reduced. Different pathogenetic processes may be operative in early diabetic glomerular and interstitial diseases.