IgAN is the primary glomerulonephritis with the highest incidence in the world, accounting for 15–32% of glomerular diseases in China 10. About 20% of patients will progress to ESRD within 20 years after diagnosis 1. Cigarette smoking is one of the most important risk factors for premature death, especially the increased morbidity and mortality 11. In China, cigarette smoking has been a common phenomenon. The mortality burden of individuals from smoking has increased in recent decades 12. The deleterious effect of smoking has been investigated in CKD patients. It was found that current smoking was an independent risk factor for progression of microalbuminuria, macroalbuminuria and ESRD among diabetic nephropathy patients. As for ex-smokers and nonsmokers, there was no significant difference for their progression of this disease 13. A retrospective study of IgAN showed that cigarette smoking was an important predictor for the progression of IgAN 5. However, another observational study found that cigarette smoking does not have a direct connection with IgAN 6. It was noticed that these studies did not include renal pathological changes and did not perform a propensity-score-matching to balance the difference between smoking and non-smoking subjects to reduce the influence of confounding factors. Therefore, whether the cigarette smoking is related to the prognosis of IgAN is still controversial.
In the current study, it was demonstrated that cigarette smoking was significantly associated with renal survival of IgAN patients. We found that comparing with non-smokers, the risk of ESRD or eGFR decreased > 50% was significantly higher in smokers among IgAN patients, 19% (40 out of 209) vs 11% (110 out of 1030), Moreover, the patients with severer renal dysfunction, were more vulnerable to cigarette smoking. Based on these results, special attention should be paid to the cigarette smoking patients who were in CKD stage 3 or 4. It was also noticed that IgAN patients who were smokers were more likely to have hypertension and renal vasculopathy changes, and a worst renal outcome compared with other patients who without hypertension or cigarette smoking. In order to decrease the obvious unbalanced influence of data, we performed propensity-score matching to make our results more convictive. From the analyses based on the matched pairs, we concluded that cigarette smoking is an independent risk factor for the progression of IgAN patients. Moreover, the relationships between cigarette smoking and hypertension, renal vasculopathy changes in biopsy were verified by the analyses of matched pairs.
Several studies reported that the adverse effects of cigarette smoking on progression of renal disease have been related to blood pressure elevation and renal hemodynamics 13,14. Several potential mechanisms may explain the relationship between cigarette smoking and the progression of IgAN. First of all, smoking induces oxidative stress by depleting antioxidants. On the other hand, IgAN is characterized by the deposition of IgA immune complexes, which leading to complement activation, increasing oxidative stress and promoting inflammatory cascade 15. That may be a plausible explanation why in our study those patients with severe impaired kidney function were more vulnerable to cigarette smoking. Second, smoking may theoretically cause renal injury through the pathogenic effect of nicotine 16,17. The direct harmful effects on vasculature promoting renal atherosclerosis are possibly a major mechanism 14. It has also been suggested that nicotine could promote the proliferation of mesangial cell and effect endothelial function. It is known that the pathological feature of IgAN is diffuse mesangial cell proliferation and mesangial matrix increase 16,17. And our analyses did show that cigarette smoking patients with more hypertension and the renal vasculopathy changes in biopsy, accelerating the process of IgAN and leading to bad renal outcomes.
Sex differences have been reported in several studies of cigarette and CKD. Some demonstrated that smoking increases the risk of kidney failure in both men and women 14. In contrast, other studies showed that male smokers were associated with a higher risk of renal dysfunction 18. However, our study found that women patients were more susceptible to cigarette smoking in patients with IgAN. Results of some studies were consistent with ours; risk associated with smoking with low exposure dose in women and men were 1.0 and 0.8, for high exposure dose, they were 1.45 and 1.24 19, and a cohort study reported that female sex was an independent risk factor after adjusting for other relevant factors 20. Because the rising rates of smoking in female individuals were observed in recent years. More attentions should be paid to these patients in clinical practice. Considering that the vast majority of smoking subjects in our study were men, larger studies were needed to clarify whether female IgAN patients are more vulnerable to cigarette smoking.
However, our study still has some limitations. First, this is a retrospective study just in a hospital center and the smoking status of all the subjects during the follow-up period were unclear. Second, we did not investigate the effect of therapeutic drugs on this smoking situation. Besides, the mean follow-up time of 61.5 months was relatively short, especially for IgAN, such a slow progressing disease.