Smoking and chronic kidney disease: seeing the signs through the smoke?

In this issue of Nephrology Dialysis Transplantation, Xia et al. report the results of a meta-analysis assessing the relation between smoking and chronic kidney disease (CKD) [1]. Their findings are based on 15 prospective cohorts including a total of more than 65 000 incident CKD patients. The summary relative risks for incident CKD and end-stage renal disease were 1.27 [95% confidence interval (95% CI), 1.19–1.35] and 1.51 (95% CI, 1.24–1.84), respectively, for ever-smokers, increasing to even 1.34 (95% CI, 1.23–1.47) and 1.91 (95% CI, 1.39–2.64) for current smokers. Remarkably, there was no association between smoking and proteinuria. Although these observations might appear to be confirmatory in nature, they highlight two important questions. One pertains to the biological rationale of the link between smoking and kidney disease, and what we can learn from these with regard to progression of kidney disease in general. The other pertains to the astonishing fact that still today, few nephrologists seem to be really concerned about the smoking habits of their patients, and little effort is done to tackle the problem. The observed relationship between smoking and incident CKD raises questions about causality. In the past, these findings were most often regarded as being at least partially confounded by coexistence with risk factors such as lower socio-demographic status, obesity, hypertension and sedentarism considering the frequent clustering of smoking with this spectrum of confounding factors. Nowadays, the concept of smoking as an intrinsic nephrotoxic factor is becoming more generally accepted. The current systematic review by Xia et al. [1] fuels this assumption by the finding that the risk of developing CKD decreases with the time elapsing after smoking cessation or increases with cumulative exposure, which suggests a dose-dependency of the cause–effect relationship [2]. In recent years, rather consistent findings from animal models and in vitro studies can help us to decipher why smoking could harm the kidneys. Smoking promotes the development of kidney fibrosis, leading to a faster decline of kidney function. Recently, standardized exposure to cigarette smoke accelerated tissue kidney injury in a rodent nephrectomy model in line with increased expression of molecular fibrosis markers and decreased expression of the anti-fibrotic microRNA miR-29b-3 [3]. Many processes that are critically involved in fibrogenesis in kidneys are negatively affected by smoking such as endothelial function, oxidative stress, activation of growth factors such as angiotensin-II and endothelin-1, impaired lipoprotein metabolism and insulin resistance [4]. As cigarette smoke contains thousands of often toxic chemicals, most of which have not been tested individually, it seems likely that many compounds exert negative effects by mostly classical mechanisms. Undoubtedly, nicotine is one of the key players in this orchestra. Nicotine has vasoconstrictive properties, which explain a transient rise in blood pressure and decrease of glomerular filtration rate and renal blood flow after exposure in healthy adults [5]. It induces epithelial and endothelial damage, has pro-inflammatory and pro-oxidant properties and activates fibroblasts in many organs [6, 7]. The kidney contains nicotinic acetylcholine receptors, and blocking of these receptors is recognized to be potentially nephroprotective [8]. Nicotine promotes mesangial proliferation and increases production of extracellular matrix in murine models of glomerulonephritis and diabetic nephropathy [9]. Other potentially relevant compounds of cigarette smoke are glycotoxins such as advanced glycation end products (AGEs), serum concentrations of which are increased in smokers [10]. AGEs mediate a faster progression of CKD, especially in patients with diabetes [11]. Also, altered patterns of DNA methylation of genes involved in the epithelial to mesenchymal transition, renal fibrosis and a more rapid decline of kidney function are being observed in smokers [12]. As these hazardous epigenetic alterations take many years to recover, this can explain ongoing negative effects despite previous smoking cessation and unfavourable outcomes in former smokers [13, 14]. Overall, the aforementioned mechanisms explain why, despite comparable kidney function, native kidney biopsies of former or current smokers show a higher degree of glomerulosclerosis, fibrous intimal thickening of small arteries and arteriolar hyalinosis than those of never-smokers [15]. It seems likely that these early histological alterations in smokers will translate into a later faster decline of kidney function and development of CKD. Mitochondrial damage in the kidneys of mice exposed to cigarette smoke during pregnancy can explain why maternal smoking in humans is associated with reduced growth of fetal kidney on serial nuclear magnetic resonance imaging even after correction for fetal volume [16, 17]. Maternal smoking is also a well-established risk factor of low birth weight, which is a recognized risk factor for the development of CKD [18]. There are arguments from experiments in rodents to believe smoking might aggravate ischaemia-reperfusion injury by enhancing oxidative stress, leading to an increased risk of acute kidney injury (AKI) [19]. Also, in observational studies active smoking increases the incidence or severity of AKI [20, 21]. Rather perplexingly, however, contradictory effects were observed for the principal compound nicotine. In a mouse model of sepsis and AKI, nicotinic agonists abrogated renal leukocyte infiltration, attenuating AKI [22]. The reported increased relative risk for progressive CKD associated with smoking in this meta-analysis is an impressive 50% [1]. Besides the negative impact on CKD, smoking also exponentially contributes to cardiovascular risk in patients with CKD, adding further insult to the injury. In a recent Japanese cohort study including more than 35 000 persons, smoking was associated with a doubled risk for overall and cardiovascular mortality, even after adjusting for age and other major cardiovascular risk factors [23]. In the SHARP cohort, current smoking was associated with a 36% enhanced risk for vascular events [24], pointing out that smoking cessation would reduce the risk for such an event twice as much as statin use. Despite this convincing evidence of harm, the nephrology community still seems poorly motivated to tackle the problem. The prerequisite of non-smoking for transplant candidates is still a matter of debate [25], with more than 50% of transplant centres reporting that they transplant current smokers. Although few studies have specifically addressed the role of pre-transplant tobacco exposure on post-transplant outcomes, in retrospective studies, tobacco exposure is associated with a decrease in patient [hazard ratio (HR): 1.4–7.4] and graft survival (HR: 1.3–8.1), and smoking cessation is associated with improvements of patient and graft survival. Despite this evidence, the European Renal Best Practice guideline does not preclude waitlisting smokers [25], and other guideline groups do not even address the issue. Research on smoking cessation strategies and its impact in general CKD patients is scant. Few nephrology symposia or congresses have smoking-related topics on their agenda. This inertion and apathy towards smoking cessation stands in sharp contrast with the promising results of cessation programmes. In the setting of primary care, a nurse-led interventional education programme for high-risk patients resulted in a significant 31% decrease of active smoking [26]. Strategies focussing on high risk groups, such as patients with diabetes or with CKD, can thus be effective. It can be argued that investing in implementation of established lifestyle changes in the broad population, such as reduction of salt intake and tobacco use, will have a substantial impact on population health. A systematic review evaluated the effects of anti-tobacco campaigns, concluding that such campaigns can substantially increase negative attitudes about smoking, reduce initiation of smoking among youth and promote smoking cessation among active smokers [27]. Increasing taxes on tobacco products leads to reduced consumption, especially in youths, with a 1% price increase leading to 0.57% decrease. Efforts to reduce smoking can thus be effective, especially when there is a combination of an individualized approach through targeted interventions by healthcare workers, and a societal approach through general measures. Both the political as the healthcare community need thus to translate the existing knowledge and evidence to the real world [28]. To conclude, evidence suggests a role of smoking on the incidence and progression of CKD, irrespective of the original native disease. Most likely this takes place through ‘classical’ pathways involved in fibrogenesis. Most important, the solid evidence of a substantial negative impact of smoking should lead the nephrological community to take action. Unfortunately, the relevance of this problem is hidden in the smoke screen produced by the pharmaceutical industry, which is trying to keep the problems relating to their products on the agenda and in the scope of awareness, rather than a lifestyle problem such as smoking. It will take intellectual bravery and leadership to keep the focus on the right spot. None declared. (See related article by Xia et al. Cigarette smoking and chronic kidney disease in the general population: a systematic review and meta-analysis of prospective cohort studies.