Several investigators have renewed interest in the role of tubulointerstitial injury in the progression of diabetic nephropathy (1,2). It was recently reported that the kidney is an important target organ for damage caused by smoking (3,4). Cigarette smoking increases carboxy-hemoglobin concentration, platelet aggregability, and fibrinogen concentration, all of which may cause tissue hypoxia and contribute to vascular damage. Smoking also has a direct deleterious effect on the proximal tubule (5). Cigarette smoking is known to promote the progression of diabetic nephropathy in clinical study (6), but its effect on tubulointerstitial injury has not been established.
We evaluated glomerular and tubulointerstitial structural findings on renal biopsy specimens taken from type 2 diabetic patients and determined the relationship between smoking and renal architecture. A total of 48 patients (32 men and 16 women) with type 2 diabetes underwent renal biopsy. Information on smoking was obtained with a self-administered questionnaire. Smoking index, defined as pack-years, was estimated by multiplying the number of packs of cigarettes smoked per day by the number of years of smoking. The severity of glomerular lesions on biopsy specimen was estimated by quantitative morphometric studies using a color image processor (SPICCA-II; Olympus, Tokyo) that measured glomerular area (GA) and mesangial ratio (MR). The MR was defined as the ratio of periodic acid Schiff–positive area to GA. The severity of glomerular lesions was divided into three grades: G1, MR <15%; G2, MR 15–25%; and G3, MR >25%. The severity of tubulointerstitial lesions (TILs) was also determined by a semiquantitative estimate of the space occupied by infiltrate or fibrosis using the following grading: T1, damaged area <10%; T2, damaged area 10–30%; and T3, damaged area >30%. Overall renal injury was categorized as group 1 (minor lesions; G1 and T1), group 2 (glomerular diffuse lesions without TILs greater than or equal to G2 and T1), and group 3 (mixed type; greater than or equal to G2 and T2). Additionally, the severity of arteriolopathy was graded on a 4-point scale of 0 to 3+. A single reader evaluating the biopsies was unaware of patient smoking status. This study was performed in accordance with the Helsinki Declaration, and written informed consent was obtained from each participant.
A total of 15 (31%) patients were classified as group 1, 22 (46%) as group 2, and 11 (23%) as group 3. The mean duration of diabetes was significantly longer in group 3 (14.2 ± 6.6 years, P < 0.05) and also tended to be longer in group 2 (9.8 ± 5.6 years) than in group 1 (6.5 ± 3.7 years). Urinary protein excretion was significantly higher in group 3 (1,881 ± 651 mg/day, P < 0.05) than in group 1 (536 ± 128 mg/day) and group 2 (729 ± 214 mg/day). Creatinine clearance, calculated using the Cockcroft-Gault formula (7), was significantly lower in group 3 (46 ± 14 ml/min, P < 0.01) than in group 1 (86 ± 24 ml/min) and group 2 (74 ± 26 ml/min). The MR was significantly higher in group 2 (21.8 ± 2.5%, P < 0.01) and group 3 (20.9 ± 7.8%, P < 0.01) than in group 1 (12.9 ± 5.3%), and the severity of TILs was significantly higher in group 3 (26.4 ± 5.1%, P < 0.01) than in both group 1 (7.3 ± 2.3%) and group 2 (7.7 ± 5.5%). Scores of arteriolopathy were significantly higher in group 2 (1.82 ± 1.01, P < 0.05) and group 3 (2.17 ± 0.83, P < 0.01) than in group 1 (1.07 ± 0.74). Smoking index was significantly higher in group 3 (29.6 ± 6.6, P < 0.05) than in both group 1 (16.8 ± 3.9) and group 2 (18.1 ± 4.5). Stepwise multiple regression analysis was used to identify independent factors of tubulointerstitial findings among the following variables: age, duration of diabetes, urinary protein excretion, creatinine clearance values, grades of arteriolopathy, and smoking index. Smoking index (β = 0.306, P = 0.004), creatinine clearance (β = −0.376, P = 0.042), and arteriolopathy (β = 0.340, P = 0.049) were independently associated with the severity of TILs (R2 = 0.636, P < 0.001).
These finding indicate an association between smoking habit and tubulointerstitial injury in diabetic nephropathy.
References
Address correspondence to Dr. M. Kanauchi, First Department of Internal Medicine, Nara Medical University, 840, Shijo-cho, Kashihara, Nara 634-0813, Japan. E-mail: [email protected].
