Risk Imparted by Various Parameters of Smoking in Japanese Men With Type 2 Diabetes on Their Development of Microalbuminuria: Analysis from the Tsukuba Kawai Diabetes Registry

Data were derived from the ongoing Tsukuba Kawai Diabetes Registry database of the Kawai Clinic, which began collecting patient information in 1995. The Kawai Clinic is a typical diabetes clinic located in a suburb of Tokyo. All type 2 diabetic patients were consecutively registered for this study at their first visit. Study protocol was consistent with the Japanese Government's Ethical Guidelines Regarding Epidemiological Studies in accordance with the Declaration of Helsinki. Data from 357 normoalbuminuric male patients with type 2 diabetes (diagnosed according to the World Health Organization criteria [14]) who had been followed for at least 3 years were analyzed. No data from female patients were included because their smoking frequency was quite low (9.4%). Patients were said to be normoalbuminuric if their first and second sample urinary albumin-to-creatinine ratios (ACRs) were <30 mg/g and were considered microalbuminuric if the ACR was ≥30 mg/g in at least two of three consecutive urine samples. The observation period was from the patients’ first clinic visit to the date they developed microalbuminuria or to their last ACR measurement. Patients with a history of cancer, high serum creatinine (>130 μmol/l), hyperpotassemia, continuous microscopic hematuria, and/or pyuria were excluded.

The mean ± SD age of our 357 study subjects was 53.7 ± 9.7 years. At study entry, 285 patients used antidiabetes agents (268 on oral hypoglycemic agents and 17 on insulin), and 43 patients used antihypertensive agents. Mean values of baseline A1C, blood pressure, total cholesterol, plasma creatinine, and calculated creatinine clearance (based on Cockcroft-Gault formula [15]) were 8.6 ± 1.9%, 126 ± 15/72 ± 10 mmHg, 5.1 ± 0.9 mmol/l, 78.1 ± 12.7 mmol/l, and 92.7 ± 26.8 ml/min, respectively. During the follow-up period, urinary albumin excretion was examined every 6 months using the turbidimetric immunoassay (Microalbumin-HA test; Wako Pure Chemicals, Osaka, Japan). Patient information regarding smoking habits was collected through face-to-face interviews with registered nurses. Smoking status was classified into one of three categories: current smokers, ex-smokers, and never smokers.

Data are expressed as means ± SD. A one-way ANOVA followed by a Tukey's honestly significant difference test was used to compare the means of the three groups. Survival curves divided by baseline smoking status were constructed using Kaplan-Meier estimates. Cox proportional hazards modeling was used to determine independent predictors of microalbuminuria. P values <0.05 were considered to be significant. All statistical analyses were performed using SPSS (version 14.0 for Windows; SPSS, Chicago, IL).

At the time of study entry, 179 of our 357 patients (50.1%) were classified as current smokers and 74 (20.7%) as ex-smokers. Current smokers smoked for a significantly longer time than ex-smokers (31.7 ± 9.6 vs. 22.7 ± 11.2 years), though pack-years did not differ statistically (43.3 ± 25.9 vs. 37.4 ± 30.8 pack-years). During the mean follow-up period of 5.7 ± 2.1 years, 106 patients (never smokers/ex-smokers/current smokers: 23/23/60) developed microalbuminuria, suggesting a crude incidence of 52.5/1,000 patient-years. Final mean values of either serum creatinine (mean 69.9 ± 13.2 mmol/l) or creatinine clearance (97.3 ± 30.7 ml/min) did not differ significantly between those who did or did not develop microalbuminuria. Only one death occurred during the observation period, that due to a neoplasm.

Kaplan-Meier analysis revealed a difference in the incidence of microalbuminuria among never smokers, ex-smokers, and current smokers, with that between current smokers and never smokers being statistically significant by log-rank testing (Fig. 1). Even after adjustment for known predictors of nephropathy (i.e., age, diabetes duration, ACR, and glycemic and blood pressure control), total and HDL cholesterol levels and alcohol consumption, differences between ex-smokers and never smokers or between current smokers and never smokers were still statistically significant (Fig. 1). Furthermore, of all quantitative parameters determined, the number of cigarettes smoked per day (1.02 [95% CI 1.01–1.03] cigarettes/day), duration of smoking (1.02 [1.01–1.03] per year), and pack-years smoked (1.01 [1.01–1.02] per pack-year) were also significant.

Previous studies (4–8) that grouped ex-smokers and never smokers together as “nonsmokers” or grouped current smokers and ex-smokers together as “ever smokers” (9–12) probably misestimated the risk of smoking because the effects of past exposure were eliminated. In fact, Kaplan-Meier curves of current smokers and ex-smokers were very close to each other, supported by Cox regression results that pack-years smoked, which is an independent and strong risk factor, did not differ between current smokers and ex-smokers.

To minimize underestimation of risk based on classification of smoking status, data concerning the number of cigarettes smoked per day, duration of smoking habit, and number of pack-years smoked should all be included. As far as we know, only two prospective studies (16,17) have investigated the relationship between the progression of diabetic nephropathy and lifetime smoking dose (pack-years of smoking); in these studies, only progression and not development of renal disease was quantified. Both studies found that the number of pack-years was a dose-dependent risk factor for the progression of diabetic nephropathy. These, combined with our results regarding development, suggest that smoking is a dose-dependent risk factor for both the development and progression of diabetic nephropathy.

In conclusion, our study clarified that smoking, both past and current, is a dose-dependent risk factor for the development of microalbuminuria in type 2 diabetic patients. Detailed smoking history including dose-related parameters should be ascertained when evaluted.

We thank Shinobu Motohashi for her excellent and accurate biochemical assays.