Mauro Cignarelli, M.D. and, Olga Lamacchia, M.D., Unit of Endocrinology and Metabolic Diseases, Department of Medical Sciences, University of Foggia, Italy

Abstract

Type 2 diabetes mellitus is the leading cause of end-stage renal disease. The smoking habit, concurrent with multiple metabolic toxicities of diabetes mellitus and metabolic syndrome, likely accelerates the multifaceted pathogenetic mechanisms of diabetic glomerulosclerosis and chronic kidney disease.

Background

Diabetic nephropathy (DN) develops in approximately 35% of type 1 diabetes mellitus (T1DM) and 15-20% of patients with type 2 diabetes mellitus (T2DM) [1], which represents the largest number of patients with end-stage renal disease (ESRD) [2]. The large majority of patients with T2DM and microalbuminuria (75-80%) have classic Kimmelstiel-Wilson lesions [3]. However, approximately 20% have nonspecific vascular changes (hyaline arteriolosclerosis and/or hyperplastic arteriolosclerosis) associated with tubulointerstitial fibrosis and minimal or no glomerular changes, suggesting that different mechanisms, commonly associated with macrovascular accelerated atherosclerosis, hypertension, and ischemia, may eventually lead to kidney dysfunction and chronic kidney disease (CKD) in diabetes mellitus, but their relationships with concurrent smoking habit has not been fully explored.

Smoking Habit, Diabetic Nephropathy, and Kidney Dysfunction in Diabetes Mellitus: Epidemiological Data

In 1978, Christiansen provided the first evidence that T1DM smokers have a higher DN risk than nonsmokers [4]. Subsequently, Sawicki et al. reported an adjusted odds ratio (O.R.) of 2.74 for every 10 cigarette pack-years for nephropathy progression in T1DM patients [5], and several different studies confirmed the increased renal risk in smokers with T1DM [6,7].

By contrast to T1DM, fewer data (and from smaller cohorts) about smoking and the risk of nephropathy are available in T2DM [8-11].

However, cigarette smoking and increased albumin excretion rate (AER) have been found to be interrelated predictors of nephropathy progression in T2DM patients despite undergoing blood pressure (BP) control [10,11]. The glomerular filtration rate (GFR) has been reported to decline approximately 55% faster in smokers compared with nonsmokers, but with no difference between the two types of diabetes [7].

Therefore, there is no doubt that cigarette smoking and diabetes when concomitant have detrimental kidney effects, significantly increasing the risk of albuminuria, CKD, and ESRD.

Kidney Damage from Smoking in Diabetes: Alterations of Glomerular Function and Structure

 As compared with nonsmokers, smoker diabetics not only have higher AER, but also a smoking dose-dependent increase in the glomerular basal membrane, without significant differences in the interstitial lesions. These effects of smoking seem to be enhanced in individuals with poor glycemic control [12,13]. Nakamura et al. demonstrated that more podocytes are excreted in the urine in smokers with microalbuminuria than in nonsmokers with microalbuminuria. Urinary podocytes disappeared after 3 years in 10/13 patients who had stopped smoking, whereas they increased in all patients who continued to smoke [14]. These data suggest that podocyte injuries associated with smoking in patients with early diabetic nephropathy may spark kidney remodeling processes.

Jaimes et al. recently demonstrated that human mesangial cells are endowed with the nicotinic acetylcholine receptors, whose stimulation induces mesangial cells proliferation and reactive oxygen species (ROS) production in a dose-dependent manner, unveiling previously unrecognized mechanisms by which nicotine may promote the progression of kidney disease [15].

Potential Mechanisms of Smoking-Induced Renal Damage Dysfunction: Pro-Oxidant and Hemodynamic Mechanisms.

The postulated smoking-induced pathomechanisms are acute effects, particularly sympathetic activation and vasopressin release (influencing BP and renal hemodynamics), and chronic effects, particularly endothelial cell dysfunction [16].

It has been hypothesized that repeated episodes of acute renal hypoperfusion induced by smoking may favor structural alterations of preglomerular vessels and glomerular obsolescence, thus leading to hypertrophy and hyperfiltration of remnant glomeruli [13,17], which would explain the elevated GFR (an early marker of kidney disease in diabetes) observed in current smokers [18].

Cigarette smoke contains more than 4,000 known constituents, including large amounts of free radicals and pro-oxidant molecules exerting an adverse influence on the survival of endothelial cells through an inhibitory effect on components of the L-arginine-nitric oxide pathway [19]. High levels of oxidative stress in smokers have indeed been shown to influence the mobilization and/or survival of endothelial progenitor cells (EPCs) in vivo [20]. In a recent study, after short-term exposure to cigarette smoke extract, Zhang et al. found a significant reduction in the endothelial NO-synthase activity of ECs together with a marked elevation in ROS and asymmetric dimethyl-arginine production [21], both recognized as a markers of oxidative stress and as risk factors for vascular diseases [22,23].

Smoking, Redox Inbalance, Renal Remodeling, and Fibrosis Signaling

Subjects with diabetes have higher levels of urinary 8-epi-PGF2α and plasma and urinary TGF-β1 (the main fibrogenetic cytokine overproduced in diabetes), while among patients with T1DM, smokers exhibited higher values than non-smokers [24,25]. Interestingly, smoking cessation produced a reduction in 8-epi-PGF2α and TGF-β1 to levels comparable with those observed in non-smokers with diabetes [25].

Remodeling is a structural rearranging-adaptive process that occurs in the long term, as a chronic response to changes in hemodynamic conditions or to the effects of injurious stimuli. This process may become a disease entity when there is loss of control of kidney remodeling, and the extracellular matrix seems to play a pivotal role in this maladaptive process, leading to CKD [26]. Therefore, excessive or prolonged signaling induced by cigarette smoking may contribute to pathologic fibrosis, scarring, and matrix deposition, i.e. remodeling, in a surprising variety of diseases, including above all diabetic nephropathy.

Smoking and GFR Reduction in T2DM

We recently reported that the proportion of patients affected by CKD is significantly higher in current smokers (20.9% versus 12.0%) than in never smokers even in the early years of the diseases, indicating a possible role of smoking in the acceleration of renal remodeling and damage. The O.R. of having CKD in current smokers is 1.93 (p = 0.04) and was still significant after adjusting for age, HbA1c, and albuminuria, and attenuated by metabolic syndrome (MS) [18].
An increase in GFR is a risk factor for progression to chronic renal disease [18,27]. We also observed that e-GFR and a marker of oxidative stress are significantly higher in no-CKD diabetic current smokers.
Therefore, it can be hypothesized that on the common fertile soil of T2DM and MS, the smoking habit may heighten renal redox stress and accelerate the decline in GFR as a consequence of uncontrolled renal remodeling.

What is the Renal Benefit Derived from Smoking Cessation?

In patients with type 1 diabetes and nephropathy with adequate control of BP, cessation of smoking significantly decreased urinary albumin excretion, although glycemia was not perfectly controlled [6]. Chuahirun et al. demonstrated that cigarette smoking cessation in T2DM patients with microalbuminuria ameliorates the progressive renal injury caused by continued smoking [28].
Unfortunately, smoking habits are not different among diabetic patients than in comparable nondiabetic populations [29,30]. Therefore, it is crucial to take the necessary aggressive-preventive measures to stop smoking in these patients.

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Please address correspondence to:
Mauro Cignarelli, M.D.
Unit of Endocrinology and Metabolic Diseases
Department of Medical Sciences
University of Foggia
Via Luigi Pinto
71100 Foggia, Italy
Tel: (+39) 0881/732212
Fax: (+39) 0881/733851
E-mail: m.cignarelli[at]unifg.it