Nephrol Dial Transplant (2017) 32: 403405
doi: 10.1093/ndt/gfw448
Advance Access publication 16 February 2017
In Focus
Smoking and chronic kidney disease: seeing the signs through
the smoke?
Steven Van Laecke and Wim Van Biesen
Renal Division, Ghent University Hospital, Ghent, Belgium
Correspondence and offprint requests to: Wim Van Biesen; E-mail: wim.vanbiesen@ugent.be
In this issue of Nephrology Dialysis Transplantation, Xia et al. ||
report the results of a meta-analysis assessing the relation be- ||
tween 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), 1.191.35] and 1.51 (95% ||
||
CI, 1.241.84), respectively, for ever-smokers, increasing to ||
even 1.34 (95% CI, 1.231.47) and 1.91 (95% CI, 1.392.64) 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 import- ||
ant 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 BIOLOGICAL CONNECTION BETWEEN
SMOKING AND KIDNEY DYSFUNCTION
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 confound-
ing 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 cu-
mulative exposure, which suggests a dose-dependency of the
C The Author 2017. Published by Oxford University Press
V 403
on behalf of ERA-EDTA. All rights reserved.
causeeffect 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, lead-
ing 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 af-
fected by smoking such as endothelial function, oxidative stress,
activation of growth factors such as angiotensin-II and
endothelin-1, impaired lipoprotein metabolism and insulin re-
sistance [4]. As cigarette smoke contains thousands of often
toxic chemicals, most of which have not been tested individu-
|| ally, 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 vasoconstrict-
||
|| ive 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 nephroprotec-
|| tive [8]. Nicotine promotes mesangial proliferation and in-
||
|| creases production of extracellular matrix in murine models of
|| glomerulonephritis and diabetic nephropathy [9]. Other poten-
||
|| tially relevant compounds of cigarette smoke are glycotoxins
|| such as advanced glycation end products (AGEs), serum con-
||
|| centrations of which are increased in smokers [10]. AGEs medi-
|| ate 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 || general CKD patients is scant. Few nephrology symposia or
negative effects despite previous smoking cessation and unfav- || congresses have smoking-related topics on their agenda. This
ourable outcomes in former smokers [13, 14]. Overall, the
|| inertion and apathy towards smoking cessation stands in sharp
||
aforementioned mechanisms explain why, despite comparable || contrast with the promising results of cessation programmes. In
kidney function, native kidney biopsies of former or current
|| the setting of primary care, a nurse-led interventional education
||
smokers show a higher degree of glomerulosclerosis, fibrous in- || programme for high-risk patients resulted in a significant 31%
timal thickening of small arteries and arteriolar hyalinosis than
|| decrease of active smoking [26]. Strategies focussing on high
||
those of never-smokers [15]. It seems likely that these early || risk groups, such as patients with diabetes or with CKD, can
||
histological alterations in smokers will translate into a later || thus be effective. It can be argued that investing in implementa-
faster decline of kidney function and development of CKD. || tion of established lifestyle changes in the broad population,
||
Mitochondrial damage in the kidneys of mice exposed to || such as reduction of salt intake and tobacco use, will have a sub-
cigarette smoke during pregnancy can explain why maternal || stantial impact on population health. A systematic review eval-
||
smoking in humans is associated with reduced growth of || uated the effects of anti-tobacco campaigns, concluding that
fetal kidney on serial nuclear magnetic resonance imaging || such campaigns can substantially increase negative attitudes
||
even after correction for fetal volume [16, 17]. Maternal smok- || about smoking, reduce initiation of smoking among youth and
ing is also a well-established risk factor of low birth weight, || promote smoking cessation among active smokers [27].
||
which is a recognized risk factor for the development of || Increasing taxes on tobacco products leads to reduced con-
CKD [18]. || sumption, especially in youths, with a 1% price increase
||
There are arguments from experiments in rodents to believe || leading to 0.57% decrease. Efforts to reduce smoking can thus
smoking might aggravate ischaemia-reperfusion injury by || be effective, especially when there is a combination of an indi-
enhancing oxidative stress, leading to an increased risk of acute ||| vidualized approach through targeted interventions by health-
||
kidney injury (AKI) [19]. Also, in observational studies active || care workers, and a societal approach through general
smoking increases the incidence or severity of AKI [20, 21]. || measures. Both the political as the healthcare community need
||
Rather perplexingly, however, contradictory effects were || thus to translate the existing knowledge and evidence to the real
observed for the principal compound nicotine. In a mouse || world [28].
||
model of sepsis and AKI, nicotinic agonists abrogated renal || To conclude, evidence suggests a role of smoking on the inci-
leukocyte infiltration, attenuating AKI [22]. || dence and progression of CKD, irrespective of the original na-
||
|| tive disease. Most likely this takes place through classical
|| pathways involved in fibrogenesis. Most important, the solid evi-
||
FROM BENCH TO BEDSIDE, OR TO THE || dence of a substantial negative impact of smoking should lead
|| the nephrological community to take action. Unfortunately, the
POPULATION? ||
|| relevance of this problem is hidden in the smoke screen pro-
The reported increased relative risk for progressive CKD associ-
|| duced by the pharmaceutical industry, which is trying to keep
||
ated with smoking in this meta-analysis is an impressive 50% || the problems relating to their products on the agenda and in the
[1]. Besides the negative impact on CKD, smoking also expo-
|| scope of awareness, rather than a lifestyle problem such as
||
nentially contributes to cardiovascular risk in patients with || smoking. It will take intellectual bravery and leadership to keep
CKD, adding further insult to the injury. In a recent Japanese
|| the focus on the right spot.
||
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 cardio- ||
|| CONFLICT OF INTEREST STATEMENT
vascular risk factors [23]. In the SHARP cohort, current smok- ||
ing was associated with a 36% enhanced risk for vascular events || None declared.
||
[24], pointing out that smoking cessation would reduce the risk ||
for such an event twice as much as statin use. Despite this con- || (See related article by Xia et al. Cigarette smoking and chronic
||
vincing evidence of harm, the nephrology community still || kidney disease in the general population: a systematic review
seems poorly motivated to tackle the problem. The prerequisite ||
|| and meta-analysis of prospective cohort studies. Nephrol Dial
of non-smoking for transplant candidates is still a matter of de- || Transplant 2017; 32: 475487)
bate [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 ||
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|

Nephrol Dial Transplant (2017) 32: 405407

doi: 10.1093/ndt/gfx006
Advance Access publication 27 February 2017

Glomerular filtration rate estimating equations: practical, yes,

but can they replace measured glomerular filtration rate?
Rajiv Agarwal
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

Correspondence and offprint requests to: Rajiv Agarwal; E-mail: ragarwal@iu.edu

Filtration of toxins is an important function of the kidney and || was by Cockcroft and Gault [1]. Cockcroft and Gault measured
estimation of the glomerular filtration rate (GFR) has long been || creatinine clearance in 249 hospitalized patients between the
||
a focus of assessment and management of patients with kidney || ages of 18 and 92 years. Using a regression equation, they
disease. However, measurement of glomerular filtration re- || related serum creatinine to creatinine clearance. They reasoned
||
mains cumbersome and expensive, therefore GFR is commonly || that generation of creatinine is dependent on age, weight and
estimated. An early attempt to estimate the filtration function || sex and that creatinine clearance was inversely related to serum
||

Published by Oxford University Press on behalf of ERA-EDTA 2017.

This work is written by a US Government employee and is in the public domain 405
in the United States.