PHWR Public Health Weekly Report

Smoking is a risk factor associated with various diseases, including atherosclerosis, cardiovascular disease (CVD), respiratory disease, metabolic disease, and malignant neoplasms. Therefore, smoking cessation is recommended to mitigate the risk of adverse outcomes and mortality in the general population. Smoking cessation has been shown to reduce the risk of chronic kidney disease (CKD) and CVD in the general population [1,-3]. According to the National Health Survey conducted among the general population in the United States, the risk of mortality from CVD decreases to a level comparable to that of non-smokers after successfully quitting smoking for more than 20 years. Similarly, the risk of mortality from respiratory diseases aligns with that of non-smokers after maintaining smoking abstinence for more than 30 years [4]. CKD is associated with an elevated risk of CVD and mortality compared to the general population. Lifestyle modifications, including smoking cessation, regular exercise, blood pressure and blood glucose control, and weight management, are recommended for patients with CKD, similar to recommendations for the general population, to reduce these increased risks [5]. Nevertheless, the level of evidence supporting lifestyle modifications recommended for patients with CKD remains low, primarily due to the scarcity of direct research conducted specifically in this patient population. In addition, differences in underlying diseases and genetic factors limit the generalizability of findings from Western CKD studies to Korean CKD patients.

The KNOW-KIDNEY is a multicenter study on CKD in Koreans, established and managed by the Korea Disease Control and Prevention Agency. Among its sub-cohorts, the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD) specifically enrolls and follows up adult patients with non-dialysis dependent CKD, with recruitment beginning in 2011 [6,7]. The primary outcome of the KNOW-CKD cohort is CKD progression, defined as progression to renal failure requiring renal replacement therapy (KFRT) or a ≥50% decrease in estimated glomerular filtration rate compared to baseline value. Furthermore, CVD development and mortality are designated as the primary outcome. The KNOW-CKD research has provided outcomes pertaining to the influence of lifestyle practices on clinical progression and complications associated with CKD in the Korean population. This study summarizes findings from KNOW-CKD on the relationship between smoking cessation, CKD progression, and cardiovascular event or mortality in patients with CKD.

A narrative review was conducted on three KNOW-CKD studies to examine the impact of smoking cessation on health outcomes among patients with CKD (Table 1) [8,-10].

Table 1 Characteristics of included studies (n=3)

Authors (yr)	Cohort (participants)	Exposure of interest	Primary outcome
Lee et al. (2021) [8]	KNOW-CKD (n=1,951)	Smoking history, smoking load, and smoking cessation duration	CKD progression
Lee et al. (2021) [9]	KNOW-CKD (n=1,914)		Coronary calcification
Joo et al. (2024) [10]	KNOW-CKD (n=1,688), UK Biobank (n=64,557)		ASCVD or mortality

KNOW-CKD=KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease; ASCVD=atherosclerotic cardiovascular disease..

1. Smoking and CKD Progression in Patients with CKD

Lee et al. [8] reported an association between smoking habits and CKD progression in 1,951 patients with CKD using KNOW-CKD data. A multivariable Cox proportional hazards model analysis showed that ever smokers had a higher risk of CKD progression than non-smokers (former smokers: hazard ratio [HR] 1.54, 95% confidence interval [CI], 1.11−2.15; current smokers: HR 1.56, 95% CI, 1.09−2.22). Among former smokers, individuals with a smoking history of 15–29 pack-years demonstrated a 1.48-fold higher risk of CKD progression compared to non-smokers, while those with a history of ≥30 pack-years exhibited a 1.94-fold higher risk (Figure 1A). Analysis findings stratified by smoking cessation duration revealed that individuals who had quit smoking for less than 10 years exhibited a 1.84-fold increased risk of CKD progression compared to non-smokers. In contrast, those who had ceased smoking for ≥10 years demonstrated a risk level comparable to that of non-smokers (Figure 1B). The risk of CKD progression is proportional to the cumulative smoking exposure and decreases with longer smoking cessation durations, suggesting that smoking cessation plays a crucial role in preserving renal function [8].

Figure 1. Hazard ratios of chronic kidney disease (CKD) progression according to smoking dose and smoking cessation duration in former smoker
(A) Hazard ratios of CKD progression according to smoking dose. (B) Hazard ratios of CKD progression according to smoking dose. HR=hazard ratio. *p<0.05. Data from the article of Lee et al. (Nicotine Tob Res 2021;23:92-8) [8].

2. The Association between Smoking Cessation and Coronary Artery Calcification in Patients with CKD

The coronary artery calcification (CAC) score (Agatston score) is a marker used to assess calcification in the heart and blood vessels based on CT imaging, serving as a predictor of CVD). Lee et al. [9] an association between CAC score and smoking in 1,914 patients from the KNOW-CKD study. In this study, CAC was defined as a calcification score greater than 0, while CAC progression was defined as an annual increase of ≥30% in the CAC score over a four-year period. The study compared former smokers and current smokers with never-smokers, categorizing participants into three groups based on cumulative smoking exposure: <10, 10–20, and ≥20 pack-years. The study revealed a positive correlation between the risk of CAC and cumulative smoking load (Table 2). Former smokers were classified into three groups based on cessation duration (<10, 10–20, and ≥20 years). Individuals who quit smoking for <10 years exhibited a 19% higher incidence of CAC compared to never-smokers, whereas those who quit for ≥10 years demonstrated an incidence comparable to that of never-smokers (Table 3) [9]. This finding underscores that smoking cessation is a critical strategy for preventing CVD in patients with CKD, emphasizing the importance of sustained interventions to promote smoking cessation.

Table 2 Association between smoking load and cardiovascular events

Outcome	Hazard ratio (95% CI)
	Former smoker			Current smoker
	<10 pack-years	10–20 pack-years	≥20 pack-years
Coronary artery calcificationa)	0.98 (0.83–1.15)	1.08 (0.92–1.28)	1.13 (1.00–1.27)	1.25 (1.10–1.42)

Outcome	Former smoker		Current smoker
	<20 pack-years	≥20 pack-years	<20 pack-years	≥20 pack-years
ASCVD or mortarlityb)	1.17 (0.65–2.10)	1.79 (1.02–3.12)	1.80 (0.84–3.87)	2.38 (1.37–4.15)

CI=confidence interval; ASCVD=atherosclerotic cardiovascular disease. ^a)Data from the article of Lee et al. (Clin J Am Soc Nephrol 2021;16:870-9) [9]. ^b)Data from the article of Joo et al. (Nephrol Dial Transplant 2024. [Epub] https://doi.org/10.1093/ndt/gfae268) [10]..

Table 3 Association between smoking cessation duration and cardiovascular events

Outcomes	Hazard radio (95% CI)
	Former smoker
	<10 yr	10-20 yr	≥20 yr
Coronary artery calcificationa)	1.19 (1.02–1.39)	1.05 (0.90–1.22)	0.99 (0.86–1.14)

Outcomes	Fomer smoker		Current smoker
	<15 yr	≥15 yr
ASCVD or mortarlityb)	1.60 (1.02–2.51)	1.13 (0.71–1.81)	2.05 (1.38–3.05)

CI=confidence interval; ASCVD=atherosclerotic cardiovascular disease. ^a)Data from the article of Lee et al. (Clin J Am Soc Nephrol 2021;16:870-9) [9]. ^b)Data from the article of Joo et al. (Nephrol Dial Transplant 2024. [Epub] https://doi.org/10.1093/ndt/gfae268) [10]..

3. The Association between Smoking and Cardiovascular Events and Mortality in Patients with CKD

An analysis of 1,688 individuals without pre-existing CVD was performed to evaluate the association between smoking cessation and the risk of cardiovascular events or mortality among KNOW-CKD participants [10]. When ever-smokers were categorized based on a 20 pack-year threshold of smoking load, the risk of cardiovascular events or mortality was not statistically significant among those with a smoking history of <20 pack-years, regardless of their current smoking status. In contrast, former and current smokers with a history of ≥20 pack-years demonstrated a significantly increased risk compared to never-smokers (Table 2). Furthermore, individuals who had quit smoking for <15 years exhibited a significantly higher risk of cardiovascular events or mortality compared to non-smokers, whereas those who had maintained smoking cessation for ≥15 years demonstrated a risk level comparable to that of non-smokers (Table 3).

The findings of the KNOW-CKD studies highlight the significance of smoking cessation in patients with CKD. Long-term smoking cessation, along with reduced cumulative smoking, is linked to a lower risk of CKD progression, CAC, cardiovascular events, and mortality. This suggests that smoking cessation may serve as a viable treatment option for patients with CKD.

Among patients with CKD participated in KNOW-CKD, former and current smokers accounted for 46.1% [7]. This is comparable to the 54.8% smoking rate in the Chronic Renal Insufficiency Cohort (CRIC) study from the United States [11]. According to the data on smoking rates in the Republic of Korea, which was recorded in 2011 and indicated a prevalence of 27.1% [12], the current smoking rate among participants in KNOW-CKD can be considered relatively low, at 15.7% [7]. This phenomenon may be attributable to lifestyle modifications, such as smoking cessation, after a diagnosis of CKD. Meanwhile, the findings indicate the need for interventions, particularly for individuals who persist in smoking at a rate greater than 15%.

The association between smoking cessation and CKD progression has not been consistently established. A CRIC study reported that the risk of CKD progression was 21% lower in former smokers and 32% lower in non-smokers compared to current smokers [13]. In contrast, the Study of Heart and Renal Protection (SHARP) study found no significant association between smoking habits and CKD progression in patients with CKD [14]. A limitation of previous studies was the lack of consideration for cumulative smoking load and cessation duration. Lee et al. [8] demonstrated that smoking load was proportionally associated with CKD progression, whereas long-term smoking cessation mitigated this risk. These results align with the findings of the CRIC studies, suggesting that they can serve as a foundation for recommending smoking cessation to patients with CKD [13].

Smoking has been identified as a significant risk factor for CVD and mortality. Previous studies have shown that patients with CKD who have stopped smoking exhibit a reduced risk of developing CVD and mortality compared to current smokers [14,15]. As posited by Duncan et al. [2,16], the risk of CVD in the general population depends on the smoking load and the duration cessation duration, even among former smokers. Consequently, it is proposed that when assessing the risk of CKD, not only the smoking status, but also the cumulative amount of smoking and the cessation period should be considered [2,16]. Similar trends were observed in the CKD population as those seen in the general population. The prevalence of CAC, cardiovascular events, and mortality showed a positive correlation with the extent of smoking. Conversely, the risk gradually declined as the duration of smoking cessation increased [9,10]. There was a difference in the effect of smoking cessation between patients with CKD and the general population. Compared to current smokers, the duration of smoking cessation required to reduce the risk of CVD or mortality to the level of non-smokers was over 15 years for individuals without CKD. In contrast, for patients with CKD, this period extended beyond 30 years [10]. These findings indicate that individuals with CKD require prolonged and consistent smoking cessation interventions to mitigate the risk of developing CVD and mortality.

The abovementioned results of the smoking study on KNOW-CKD are subject to several limitations. First, the smoking information was collected only in the baseline survey and did not reflect changes in smoking status during the study period. Second, since electronic cigarettes were not widely available at the start of the KNOW-CKD studies, information on them was not included, which may have affected the results with potential bias. These limitations should be considered when interpreting and generalizing the results of the study.

This study reviewed studies on the effects of smoking cessation on CKD progression, CVD, and mortality in Korean patients with CKD using KNOW-CKD data. The findings of this study indicated that the risk of CKD progression, CAC, CKD, and mortality risk increased with smoking load. However, the duration of smoking cessation was found to be inversely associated with this risk. However, the existing literature on this topic is limited, highlighting the need for further research. Furthermore, effective policy development is imperative to promote and sustain smoking cessation among patients with CKD. It is expected to contribute to the promotion of health and the management of disease in patients with CKD.

Ethics Statement: Not applicable.

Funding Source: This work was supported by the research program funded by the Korea Disease Control and Prevention Agency (2011E3300300, 2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, 2016E3300201, 2016E3300202, 2019E320100, 2019E320101, 2019E320102, and 2022-11-007).

Acknowledgments: Authors thank all the KNOW-CKD investigators and clinical research coordinators for their dedication to this cohort study.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Conceptualization: YSJ, SHH. Data curation: YSJ. Formal analysis: YSJ. Funding acquisition: KHO. Investigation: YSJ, SHH. Methodology: YSJ, SHH. Project administration: SHH, KHO. Resources: KHO. Software: YSJ. Supervision: SHH, KHO. Validation: SHH, KHO. Visualization: YSJ. Writing – original draft: YSJ. Writing – review & editing: SHH, KHO.