Smoking and Chronic Kidney Disease in Healthy Populations

The objective of this review is to explore the link between smoking and the development of chronic kidney disease (CKD) in generally healthy populations without pre-existing renal dysfunction such as diabetic nephropathy. Twenty-eight epidemiological studies concerning the renal effects of smoking in the general population were collected from the MEDLINE database and were reviewed for indications of proteinuria and/or the decline of glomerular filtration rate (GFR), and evaluated on the level of evidence and the quality of the study. Sixteen of the 28 studies were cross-sectional in design. Most articles had some weakness in scope, such as the 6 articles which did not fully exclude DM patients from the subjects, the 4 that did not consider the effects of ex-smoking, and the 3 that focused on only a small number of subjects. From these cases, it is difficult to draw firm conclusions. However, proteinuria or microalbuminuria was persistently high in current smokers; as much as 5-8% or 8-15% respectively, which was up to 2 to 3-times the rate of lifelong non-smokers. On the other hand, only 5 studies broader in scope detected any decline of GFR in smokers, while 9 other studies suggested a higher GFR in smokers than in non-smokers. Two good quality studies showed an even a significantly lower risk of a decreased GFR in smokers. These paradoxical CKD markers in smokers, i.e., a higher appearance of proteinuria with a higher GFR, could be a focus for further studies to reveal the underlying reasons for smoking-induced CKD. Workplaces may be an excellent place to study this subject since the long-term changes in renal function of smokers can be observed by collecting data in the annual health check-ups mandated at places of employment.


Background
The adverse renal effects of smoking were first demon strated in patients with diabetes mellitus, and successive ly in those with primary kidney disease such as polycys tic kidney, glomerulonephritis and lupus nephritis, and those with primary hypertension (1)(2)(3)(4) of REnal and vascular ENd stage disease) study group (5) showed that smoking was associated with an excessive urinary albumin excretion in inhabitants without dia betes in a Dutch community. This study suggested that smoking induces chronic kidney disease (CKD) as mani fested by proteinuria and/or lowered glomerular filtra tion rate (GFR) even in generally healthy adults.
In 2007, Jones-Burton et al. (6) reviewed 17 articles concerning the association of cigarette smoking with the incidence of CKD and concluded that smoking is a significant risk factor for CKD, but that the depth of the correlation remains obscure due to the vast heterogene ity in the source populations and in the methods used to measure the outcomes. Furthermore, most of the studies included a considerable number of subjects who were di abetic. Since the renal effects of smoking are more wellknown in patients with diabetic nephropathy, the impact of smoking in healthy adults without that renal dysfunc tion is even more difficult to determine. We tried to eluci date, therefore, the possible association between chronic smoking and CKD in generally healthy populations by re viewing previous studies conducted on this matter.

Review of the Literature
The literature concerning the renal effects of cigarette smoking in generally healthy populations was researched on the MEDlINE database using a PubMed interface on April 8, 2011. All articles published in English from 1966 onwards were searched using the following combination of terms: smoking AND (proteinuria oR albuminuria oR kidney diseases). 2,881 articles were retrieved in this man ner. According to the titles, and abstracts if available, 51 original articles describing epidemiological studies con ducted in the general population regarding the preva lence and incidence of the signs of CKD were selected and examined in the full length papers. Excluding duplicated articles, or those conducted mainly on diseased patients, or those not noting CKD with regards to smoking, or those not considering the effects of confounding factors, and including two recently published articles of our own (7), 28 articles were reviewed. All papers were evaluated for the level of evidence (loE) according to the criteria proposed by the Agency for health Care Policy and Re search (AhCRP) in 1993, and for the quality of study based on items selected from the recommendations for good analytical epidemiological studies (8,9).
The items are shown in Table 1 : 1) the selection of sub jects, for the definition in accordance with the goal of this review and the appropriateness of the mother popu lation, 2) the size of the study population, 3) the duration of observation in cohort studies, 4) the definition of ex posure (smoking status in this review), 5) the measure ment of outcome (proteinuria and renal function), 6) statistical analyses, and 7) considerations of confounding factors. Each item was graded as "good", "fair", or "accept able" where appropriate. The study subjects should be generally healthy for this review, and thus the exclusion of subjects who may have pre-existing renal dysfunction, especially those due to primary kidney diseases or diabetes mellitus, is required for a "good" study. At least, the subjects should be re cruited from communities or workplaces even though those exclusions were not fully completed as shown in "acceptable". Appropriateness is graded as "good" when the participating subjects were randomly collected from the mother population or consisted of 70% or more of the population. Non-arbitrary collection of the subjects such as volunteers for health screenings is graded as "fair".
Assuming the prevalence of proteinuria to be 5% in smokers and 3% in non-smokers, and the smoking rate to be 30% of male and 15% of female subjects, the minimum sample size required to detect a significant difference is estimated to be 400 in men and 800 in women, which is graded as "fair". A sample size that is ten times larger is graded as "good", and the sample size of 100 men and 200 women or more is graded as "acceptable". For the range of the study (smoking in this review), the effects of past smoking should be considered, and thus the studies classifying the subjects only into current smokers or non smokers are graded low as "acceptable". For the measure ments of proteinuria or albuminuria as the outcome, quantitative measurements of these parameters in urine are graded as "good", and semi-quantitative measure ments using a dipstick are graded as "fair". For renal func tion, using a well standardized equation for estimating GFR, such as that proposed by the modification of diet in renal disease (MDRD) study group (10), or by the Japan Society of Nephrology (JSN) is graded as "good" as well as the actual measurement of GFR or creatinine clear ance (Ccr). Ccr estimated by the Cockcroft and Gault (CG) equation (11) or simply serum creatinine (Cr) concentra tion for the index of renal function is graded as "fair" be cause of the lower validity for estimating real GFR values. Confounding factors should be matched or adjusted for using a multivariate analysis, and consideration of de mographic factors is required for "acceptable". As a final point ,, the articles which are graded as "good" in all the items are classified as "A", those graded as "acceptable" in any of the items are classified as "C", and the remaining are classified as "B". Sixteen of the 28 articles reported the effects of smoking on proteinuria or albuminuria (7, 12 26), and 21 reported the effects on renal function (7,12,14,15,17,21,22,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)).

Proteinuria or Albuminuria in Smokers
As revealed in Table 2, 13 of the 16 studies on proteinuria or albuminuria were cross-sectional in design (loE of 3). only one study was classified as "A" in the quality and 9 were classified as "B" because of the use of a dipstick method for detecting proteinuria (3 articles) or albumin uria (1 article), not fully excluding DM patients from the subjects (3 articles), or not-randomized selection of the subjects (2 articles). Six studies were classified as "C": 3 ar ticles because of not considering ex-smoking, 2 because of the small number of subjects and one cohort study be cause of the short period of observation.
Therefore, firm conclusions cannot to be drawn from those studies, but the following has been observed: 1) proteinuria or microalbuminuria was found in 5-8% (7, 23, 24) or 8-15% (14,17,21,25) respectively, of current smokers being generally higher than in non-smokers, with up to 2 to 3-times higher than the rate of lifelong non-smokers, and 2) smoking-induced proteinuria is detectable even in middle-aged persons from the working populations (7,17,22,24,25), but 3) it is found more frequently in those with a higher BP (12,24), higher blood glucose (12) and a higher age of 50 years or older (24).

Renal Function in Smokers
As shown in Table 3, 10 of the 21 studies on renal funct ion are follow-up designs (loE of 2). Three studies were classified as "A" for the quality and 9 were classified as "B" because DM patients were not fully excluded (5 articles) or outcomes measured by the Ccr by the CG equation or serum Cr concentration (4 articles). Including 6 followup studies, 9 articles were classified as "C": 3 articles be cause of the small number of the subjects, 3 because of not considering ex-smoking, 2 because of not excluding mild CKD patients in the follow-up studies in which renal failure was set as the endpoint, and 1 because of short pe riod of the observation.
The overall outcomes in the studies on renal function are conflicting. only 5 studies with grade A or B in qual ity (27,29,31,37,38) detected a significant effect of smok ing on the decline of renal function, which was also suggested in other 6 studies with grade C (12,26,28,30,32,33). These studies were all conducted in community populations, some of those included many elderly per sons (27,28,37,38) or CKD patients (32,33). Yamagata et al. (38) followed 124,000 inhabitants aged 40 years or older in a community in Japan for 10 years, excluding all those showing CKD signs beforehand, and observed that smoking caused a significant but only 10% increase in the risk for a declining GFR to the level of less than 60 ml/ min/1.73m. on the other hand, 9 studies with any grade in quality even showed a higher GFR or Ccr in smokers than in non-smokers, especially those conducted in working populations (7,17,22,25,35,36). A significantly lower risk of a low GFR was even observed in current smokers (17,25). No difference was observed in age-related decline of GFR or Ccr among current and former smokers, and life time non-smokers (7,15). one study showed even a more modest decline of GFR in smokers than in non-smokers during a 5-year period (35). In addition to the generally low loE and quality of the literature, this article has some other limitations. The lit erature was collected only from the MEDlINE database, and some important articles may thus have been over looked. The methods and manner of quality evaluation of the articles in this review have not been approved by experts other than us, which might have added some arbitrariness to the evaluation. But, in these specific cir cumstances, this review reveals some peculiar paradoxi cal findings of CKD signs in smokers in healthy popula tions, i.e., a persistently high appearance of proteinuria often accompanied with an elevated GFR.

Significance of the Paradoxical CKD Signs in Smokers
Yoon et al. (25) in Korea has already pointed out the paradoxical CKD signs in a cross-sectional observation in 35,288 participants of a health screening program, and named "the different effect of smoking on GFR and pro teinuria in a healthy population". They mentioned that the association of smoking status with GFR was different between those showing a GFR of 50 ml/min/1.73m 2 or above and those with a lower GFR. In those with the rela tively high GFR, smokers showed a higher mean GFR than non-smokers, but an inverse association was observed in those with the low GFR, i.e., smokers have a lower GFR than non-smokers. From these findings and the limited appearance of proteinuria even in smokers, Yoon et al. proposed a hypothesis that most smokers from the gen eral population do not show deteriorations of renal func tion even though they showed an elevated GFR, while only a small, especially susceptible subset of the popula tion would show a lowered GFR and proteinuria. howev er, this hypothesis has not yet been confirmed.
Possible factors underlying the development of CKD in smokers were extensively discussed by orth and hallan (2) such as hypoxia, heavy metals in tobacco smoke, in trarenal vasoconstriction, oxidative stress and inflamma tory process. Although the exact variable has remained uncertain, the intraglomerular hypertension caused by the intrarenal hemodynamic changes due to nicotine in cigarette smoke may be the most plausible reason. The high GFR in smokers may thus be a reflection of glomeru lar hyperfiltration following the intraglomerular hyper tension and the early sign of renal damage like that ob served in the early stage of diabetic nephropathy (39). If so, the high GFR in smokers may eventually decrease to a low level with continued smoking and cause proteinuria. however, this has not been confirmed either since longi tudinal observations on GFR have so far failed to identify a more marked decline of GFR in smokers than in non smokers (34,35).

Advantages of Studies in Workplaces
The number of CKD patients is estimated to be 13 mil lion or more in Japan, which is more than 10% of the national population. however, it has not been well rec ognized among healthcare experts, especially those en gaged in preventing activities for life-style diseases at worksites. The population of Japan is aging rapidly and so is the workforce, and most workplaces are predicted to have as many as 30% or more workers aged 60 years or older in 2050. Since the renal toxic effects of smoking are more predominant in elderly persons, healthcare experts at worksites may face the far-ranging and profound im pact of smoking-induced CKD in the near future.
The aging of the working population, on the other hand, may provide healthcare experts at worksites with a greater chance of observing the long-term annual chang es in renal function in smokers throughout middle-age to the age of 70 years or longer. Therefore, workplaces may have special merits of revealing a more conspicuous decline of GFR in smokers once showing a higher GFR as compared to non-smokers from the data collected by the annual health check-ups mandated by the workplace. healthcare experts at workplaces should pay more atten tion to smoking-induced CKD.