Renal Impairment in Chronic Cigarette Smokers
GIOVANNI GAMBARO,* FABIO VERLATO,t ALESSANDRO BUDAKOVIC* DARIO CASARA, GIORGIO SALADINI, DORELLA DEL PRETE* GISELDA BERTAGLIA* MAURIZIO MASIERO,* SIMONE CHECCHETTO,* and BRUNO BAGGIO* *Jnstjtute of internal Medicine, Division of Nephrologv and C’NR Center on Aging, tAngiology Seri’ice, Nuclear Medicine Service, and Central Laboraton’, University Hospital, Padua, Italy.
Abstract. To determine the effect of chronic cigarette smoking 256.54 ± 60.14 mI/mm per 1.73 m2; t = 3.52, P < 0.001). on renal function, a cross-sectional study was carried out with MAG1 clearance was significantly correlated with age and 30 subjects who had no known vascular disease risk factor smoking. The renal dysfunction was associated with an in- other than cigarette smoking, and 24 age- and sex-matched crease in plasma endothelin-l concentration (21.56 ± 1.15 controls without any vascular risk factor including cigarette pmollL versus 25.01 ± 3.21 pmollL; t = 5.00, P < 0.001). smoking. Renal function by radionuclide studies of renal Former smokers as well had similar, although milder, abnor- plasma flow, GFR, and plasma endothelin- 1 concentration was malities. In conclusion, cigarette smokers manifest an impair- determined. Compared with nonsmokers, smokers had a renal ment of renal function, suggesting that smoke may have a function impairment characterized by a normal GFR and a detrimental effect on renal function. (J Am Soc Nephrol 9: significant reduction in renal plasma flow as reflected by 562-567, 1998) MAG3 clearance (199.20 ± 58.85 ml/min per 1 .73 m2 versus
Cigarette smoking is a major risk factor for vascular disease; it versity Hospital to evaluate the relationship between systemic induces a variety of effects on the vascular and hormonal atherosclerosis and renal function. The findings obtained by ana- systems and is involved in the development of atherosclerosis, lyzing renal function in a group of subjects who had no known thrombogenesis, and vascular occlusion ( I ,2). The mechanisms vascular disease risk factor other than cigarette smoking suggest of smoking-related arterial damage have not yet been defined; that chronic cigarette smoking has adverse renal effects. however, a sympathetic stimulation, with consequent release of the neurotransmitter norepinephrine (3), and morphologic and Materials and Methods functional endothebiab changes, characterized by intimal Patients smooth muscle cell proliferation and alterations in endothelial The subjects who constitute the basis of this study were recruited prostacyclin synthesis and endothelial-derived vascular tone from among all of the patients older than age 55 referred to the regulators (4), seem to play an important role. Although the angiology outpatient service of Padua University Hospital from 1993 effect of smoking on peripheral vascular beds is well docu- to 1995. Patients were referred to evaluate symptoms of possible athero- mented, less information is available regarding its effect on the sclerotic origin (e.g. , general dizziness, transient amaurosis, transient kidney. A recent preliminary report suggests that smoking- ischemic attack, intermittent claudication), as well as for vein problems (e.g., varices, thrombophbebitis). A total of 400 patients agreed to panic- related hemodynamic events may have an acute influence on ipate in a study project to evaluate the association between cardiovascular renal function (5): other studies have proposed that smoking in risk factors, peripheral vascular disease, and renal function. Of these, only diabetes mebbitus is associated with the development and/or patients without laboratory evidence or personal history of nephropathy progression of diabetic nephropathy (6). However, it is not were considered. Namely, in all recruited subjects, the serum creatinine known whether chronic smoking in itself has any adverse level was < 136 jsmol/L, and urinalysis did not disclose hematuria, effect on renal function in a kidney not affected by specific abnormal sediment, or proteinuria. Proteinuria was ruled out on the basis diseases. To address this issue, data were collected from a cross- of routine stix analysis (Mubtistix, Miles) negativity in two extemporary sectional, clinical-based investigation carried out at Padua Uni- morning urine collections performed on different days. Furthermore, all available medical records obtained from patients and from a search of the files of this hospital were checked to exclude renal pathology. Patients for whom it was not possible to obtain enough confidence in ruling out Received April 28. 1997. Accepted October 13. 1997. previous renal pathology because of the lack and/or unreliability of Preliminary data from this study were presented at the 33rd EDTA/ERA Congress. Amsterdam. June 1996, and published in abstract form in Nephrol records were not enrolled. Dial Transplant II : A72. I 996. To exclude any interference of renal hemodynamics, subjects on Correspondence to Dr. Bruno Baggio, Istituto di Medicina Interna, Policlinico diuretic, 3-bbocker, angiotensin-converting enzyme inhibitor, or cal- Universitario. via Giustiniani 2. 35120 Padova, Italy. cium channel blocker treatment were excluded. Furthermore, because b046-6673/0904-0562$03.00/() the goal of the present study was to evaluate the role of smoking in Journal of the American Society of Nephrobogy kidney function, only those patients who had no or one cardiovascular Copyright (0 1998 by the American Society of Nephrobogy risk factor, cigarette smoking, were considered. Therefore, patients Renal Impairment in Chronic Cigarette Smokers 563 with hyperlipemia (cholesterol >6.0 mmollL and/or triglycerides Table 2. Atherosclerosis score in lower limb arteries > I .9 mmolfL), with systemic diseases predisposing to vasculitis or Atherosclerosis Raynaud’s phenomenon, as well as subjects with BP repeatedly higher Stenosis Winsor’s Index ATS Score Involvement than 155/90 mmHg, were excluded. This BP cutoff is lower than that generally considered to define “arterial hypertension” (160/100 or Null-moderate <49% >0.9 0 I 60/95 mmHg) in the elderly and was chosen to improve our confi- Severe >50% <0.9 2 dence in excluding both systolic and systodiastolic hypertensive pa- tients. Also, subjects with diabetes or a family history of first-degree relatives with diabetes were discarded. No oral glucose tolerance test was performed, but all available medical records of patients were Table 3. Atherosc lerosis global score checked, and fasting glycemia and glycosuria in two morning urine collections were evaluated. None had abnormal glucose values. Atherosclerosis Carotid ATS Lower Limb Artery Global ATS Involvement Score ATS Score Scorea In summary, we enrolled 54 subjects: 24 nonsmokers considered as controls and 30 cigarette smokers, of which 1 3 were current smokers Null-mild 0 0 0 (> 10 cigarettes/d since young adult age) and 17 were former smokers Moderate 1 0 1 who had quit smoking for 5 to 7 yr and were not exposed to passive Severe 2 2 2 smoking. According to the study protocol, the patients underwent a series of appropriate diagnostic procedures in the blind, including a Defined according to the most involved arterial district. complete physical evaluation and biochemical profile, ultrasonogra- phy with Doppler analysis for the localization of peripheral vascular disease, and renal function evaluation. Body mass index was calcu- lated. Laboratory studies were performed in a fasting blood sample an equivalent hippuran clearance, and therefore an equivalent renal and included cell count; hemoglobin concentration; prothrombin time plasma flow, was proposed because the two clearances show a highly and partial thromboplastin time: electrolyte concentration; iron; total significant correlation (r 0.95) (12,13). However, considering the protein; protein electrophoresis; bilirubin; alkaline phosphatase; pharmacokinetic differences that exist between the two agents, in agree- transaminases; creatine phosphokinase; urea nitrogen; uric acid; cre- ment with most investigators we considered it more appropriate to com- atinine; glucose; total, HDL, and LDL cholesterol; and triglycerides. pare MAG1 clearances with normal values, rather than convert them to a On morning fresh urine, specific gravity, pH, Multistix parameters, corresponding hippuran clearance. The scintigraphic tests were carried and the high-power field microscopy of the sediment were executed. out 24 to 48 h apart; 200 MBq of the radiopharmaceutical (MAG3, Among these selected patients, none had symptoms or personal his- Mallinckrodt Medical, Petten, Holland, and DTPA, Sobco-Sorin, Salug- tory suggestive of coronary artery disease and all had a normal resting gia, Italy) were prepared and standardized following the operating pro- electrocardiogram. Furthermore, none had a family history of prema- cedure included in the labeling kits before injection. Preparations with a ture vascular disease. radiochemical purity <97% were discarded. Atherosclerotic lesions (ATS) in the carotid (7,8) and lower limb Plasma endothelin- 1 (ET- 1) concentration was also determined in (9) arteries were scored as shown in Tables 1 and 2, respectively, and blood samples drawn between 8 and 8:30 am. The analysis was carried an ATS global score (Table 3) was obtained in every subject. Ac- out in duplicate with an RIA kit (Peninsula Laboratories, Belmont, CA). cordingly, 16 of 30 cigarette smokers and 8 of 24 nonsmokers had Results are expressed as the mean of the two determinations. moderate-to-severe peripheral atherosclerosis localization (ATS score: 1 and 2, respectively), a difference that does not reach statistical Statistical Anah’ses significance. Renal function was evaluated between 8 and 9 am., after Data are expressed as mean ± SD. Statistical analysis was per- at least 8 h of nonsmoking, by: (1) clearance of technetium-99m- formed by t test for unpaired variables, one-way ANOVA, the Bon- diethylenetriamine penta-acetic acid (DTPA), which is filtered only ferroni test for subgroup comparisons, and by simple correlation. The by the glomerulus, to measure GFR (10); and (2) clearance of tech- relationship between MAG1 clearance and GFR as dependent vari- netium-99m-mercaptoacetyltrigbycine (MAG3), which was performed ables; other clinical and demographic variables (ATS score, actual or by the Bubeck method (I I ). MAG1 is considered a valuable and previous smoking habits, age, gender); and biochemical independent sufficiently accurate probe in the clinical setting for the noninvasive variables (serum levels of ET-l total, HDL, and LDL cholesterol; and investigation of renal function. Its active transport by the renal tubular triglycerides) were analyzed by a step-down multiple regression cell accounts for 89% of the total clearance; the remaining portion is model. Comparisons of f3 coefficients were performed with the t test. explained by glomerular filtration. Although MAO3 is not as accurate Partial multiple correlation was also carried out between MAO1 as hippuran for estimating renal plasma flow (MAG3lhippuran clearance clearance or GFR, age, and smoking (actual/former). Statistical sig- ratio is approximately 0.60), the conversion of MAO3 clearance values to nificance was defined as a P value <0.05.
Results Table 1. Atherosclerosis (ATS) score in carotids Clinical and biochemical parameters are summarized in Ta- Atherosclerosis ble 4. Smoker and nonsmoker groups were well matched for a Stenosis ATS Score Involvement number of demographic, cardiovascular, and metabolic van- ables. In fact, average age; sex distribution; BP; body mass Null-mild 19% 0 index; total, LDL, and HDL cholesterol; and triglyceride blood Moderate >20 ± 49% 1 levels were similar in both main groups and subgroups. The Severe 50 ± 74% 2 parameters of the biochemical profile not shown in Table 1 Very severe 75% 3 were all in the normal range in all subjects. 564 Journal of the American Society of Nephrology
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According to the criteria reported by Nally et al. (14), no 400 A significant reduction in perfusion indexes and/or asymmetry A - A “ A between the separate renogram profiles was observed in any .-... U -C subject, which thus excluded major renal vascular pathology. A .. #{149} A In five subjects (three smokers, two nonsmokers) in whom AA A E scintigram findings were dubious, captopnil scintigraphy ruled E out major renovascular disease. 200
Although GFR did not differ between nonsmokers and CO CO smokers, the latter showed a significant reduction in MAO1 C’ clearance (Table 4); no significant difference in these param- eters was observed between former and current smokers. To determine whether MAG1 clearance and GFR levels were related to other clinical and demographic factors besides so 55 60 65 70 75 80 85 90 95 100 smoking, step-down multiple regression analysis was per- Age (years) formed with MAG1 clearance or GFR as dependent variables. Figure 1. Dispersion plot of mercaptoacetyltriglycine (MAO3) clear- Age ( 3 = -4.89 ml/min per 1.73 m/yr, P = 0.001), actual ance values versus age. Regression curves were obtained by multiple smoking (13 - 102.49 ml/min per 1 .73 m2/yr, P = 0.000), regression analyses (r = 0.71; F = 14.41: P = 0.000). The difference and previous smoking (/3 = -62.94 ml/min per 1 .73 m2/yr, between partial regression coefficient f3 is I 8.79 mb/mm per I .73 m2
P = 0.000) were the only statistically significant and indepen- (t = 6.68: P = 0.000). U, , actual smokers; #{149},- - - -, former smokers; nonsmokers. dent variables influencing the MAG1 clearance (r = 0.78; F = 10.5; P = 0.000) (Table 5). Moreover, the decrease in MAG1 clearance was lower in the former than in the current smokers Table 6. Multivariate regression analysis of the relationship I3 18.79 mI/mm per 1.73 m2/yr; t = 6.68; P = 0.000) between GFR and other clinical and demographic (Figure 1). The hypothesis of an interaction between smoking variables0 and age was also tested, but it was not significant (/3 = 0.78 ml/min per 1 .73 m2/yr; P = 0.79). The partial correlation that GFR Partial Regression . , .. . PVabue was obtained confirmed the significant inverse relationship (mI/mm per 1.73 m) Coefficment (SEM) between MAO1 clearance and age (r = -0.53; P = 0.000), and Age (yr) - 1 .55 (0.64) 0.020 smoking (r = -0.69; P = 0.000). Actual smoker - 1 1 .44 ( 1 0.67) 0.279(NS) Multiple regression analysis with GFR as the dependent Former smoker -2.73 ( 10.60) 0.799(NS) variable did not give an adequate model (F = 1 .08; r = 0.04; Gender 3.67 (9.60) 0.703(NS) NS), but showed that only the relationship between GFR and ATS 1 -4.54 (10.16) 0.657(NS) age was significant (f3 = - 1 .55 ml/min per 1 .73 m2/yr; P = ATS 2 7.71 (9.47) 0.452(NS) 0.020) (Table 6). The partial correlation that was obtained Intercept = 200.98; F = 1.08; R2 = 0.13; R = 0.36; confirmed this relationship (r = -0.28; P = 0.047) and further P = 0.39 (NS) excludes a correlation between GFR and smoking (r = -0.04; NS). When the subjects were subdivided into nonsmokers and a The analysis was carried out on 54 subjects (24 nonsmokers).
Table 5. Multivaniate regression analysis of the relationship smokers, and the data analyzed by simple correlation, the same between MAO1 clearance and other clinical and trend was observed only in the nonsmokers (r = -0.56; P = demographic vaniables#{176}’ 0.004), whereas the relationship disappeared in the smokers MAO1 clearance Partial Regression Value (r -0.11; NS). (mllmin per 1.73 m2) Coefficient (SEM) Finally, compared with nonsmokers, smokers showed a higher plasma ET- 1 concentration. In an attempt to improve Age (yr) -4.89 (1.39) 0.001 the models to describe MAG1 clearance and GFR, multiple Actual smokers - 102.49 (19.69) 0.000 regression analysis was performed adding ET- 1 to the previous Former smokers -62.94 (19.47) 0.000 independent variables (gender, age, smoking habits, ATS Gender -8.74 (17.58) 0.62l(NS) score), as well as serum levels of total, HDL, and LDL cho- ATS 1 -35.08 (19.56) 0.080(NS) lesterol, and triglycerides. Concerning MAG1, the derived ATS 2 -20.68 (18.28) 0.296(NS) model was improved (F = 22.7; P = 0.0000; r = 0.83; r Intercept = 618.1; F = 10.5; R2 = 0.61; R = 0.78; 0.69) and revealed that MAO1 clearance is influenced by ET- 1 P = 0.000 as well (P = 0.0001), whereas the other metabolic variables were not significantly correlated. On the contrary, the model of a The analysis was carried out on 54 subjects (24 nonsmokers) and is the result of a step-down multiple regression by excluding GFR was not improved, and namely ET- 1 was not a statisti- the less significant variables. cally significant determinant. 566 Journal of the American Society of Nephrobogy
Discussion relationship between GFR and age in our smokers suggests that The present study demonstrates that chronic cigarette smok- the mechanism of the smoking effect on renal function is different ens have a renal function impairment characterized by a normal from that of the age-related one. GFR and a significant reduction in renal plasma flow as evi- The hemodynamic renal profile of smokers is similar to that denced by MAG1 clearance. observed in hypertensive arteriolar nephrosclerosis, in which The possibility that a selection bias could explain the present the earliest impairment in overall renal function is a reduction results seems unlikely. Although we considered only subjects in renal plasma flow and a usually normal GFR (17). However, admitted to an angiology service (i.e. , who might not correspond because none of the smoking subjects was hypertensive and to the general, but rather to an atherosclerotic population), many mean arterial pressure was not different among groups, we of these patients were referred for trivial vascular symptoms that believe that the alteration we describe is really a smoke-related only hypothetically were atherosclerotic in origin; indeed, only 24 dysfunction. of 54 patients showed a moderate or severe peripheral atheroscle- An attempt was made to disclose pathophysiologic mecha- rosis on ultrasonography and Doppler analysis. Therefore, the nisms responsible for the renal alteration in smokers. A number study subjects constitute a mixed group, which might resemble the of circulating and local vasoactive factors were found to be general, >55-yr-old population. Furthermore, smoker and non- altered in smoking subjects, which might play a role in the smoke-associated effect on renal flow (3,18-24). Among smoker groups were well matched for a number of demographic, these, ET- 1 is very interesting. It is known that ET- 1 is an cardiovascular, and metabolic variables. In fact, average age; sex important mediator of pathophysiologic alterations in renal distribution; BP; body mass index; total, LDL, and HDL choles- hemodynamics. It is a very powerful vasopressor agent, five- terol: and triglyceride blood levels were similar in both main fold more potent than angiotensin acting on both afferent and groups and subgroups:. Moreover, the global ATS score did not efferent arterioles. In rats, ET-l infusion constricts the efferent correlate with renal function. These findings argue against bias more than the afferent arteriole, with an attendant increase in introduced from preexisting vascular disease. glomerular capillary pressure and a decrease in the ultrafiltra- Until now, investigators and clinicians essentially have fo- tion coefficient (25,26). In dogs, ET-l reduces renal blood flow cused on the role of active and passive smoking as a risk factor and increases renal vascular resistance, without producing any for arterial damage, a risk factor whose magnitude is compa- significant modification of glomerular filtration at pathophys- rable to the other well known vascular risk factors: hyperten- iologic concentrations (27). Furthermore, ET-l has potent mi- sion and hypercholesterolemia. Indeed, smoking is strongly togenic and atherogenic activities on vascular smooth muscle associated with coronary, cerebral, and peripheral vascular and mesangial cells (28). Thus, ET-l might explain the full disease ( 1,2). This is the first report showing an adverse effect picture of renal changes observed in active and former smoking of chronic smoking on kidney function. In fact, only a few subjects, i.e. , both functional (present data) and morphopatho- studies have addressed the acute effect of smoke on renal logic alterations (renal arteriolar thickening) reported by previous function (5) and the possible aggravating risk of smoke on autopsy studies (29,30). Indeed, the plasma concentration of ET-l diabetic nephropathy (6). was reported to be increased in smokers (24), and our study, The renal dysfunction was also observed in subjects who showing higher plasma values of ET-1 in smokers and, in panic- quit smoking, suggesting that functional, initially reversible ular, in the actual smokers, confirms this. Furthermore, ET- 1 changes probably became fixed after years of smoking. This emerged as a significant determinant of MAG1 clearance. This observation, the 8-h washout from smoking before performing finding strongly supports the hypothesis that ET-l has a signifi- clearance studies, and, finally, evidence that a number of cant role in smoke-associated renal impairment. smoke-induced acute phenomena are shorter, i.e. , the endothe- Although carbon monoxide-induced hypoxia, nicotine-in- hal release of the von Willebrand factor ( 15) and of ET- 1 ( 16), duced a 1-adrenergic stimulation, and oxygen-free radicals do not support the idea that the renal alteration observed in may all concur to explain the increased plasma level of endo- actual smokers might be due to an acute smoke effect. thelin in current smokers (28), the increase in ET-l observed in The MAG1 clearance values were statistically explained by former smokers might be secondary to the irreversible renal clinical and demographic factors: age and smoking habits. In the vascular damage described in cigarette smokers (29,30), or to age range considered (55 to 85 yr), subjects showed a reduction in a subtle hypoxia due to mild chronic obstructive pulmonary MAG1 clearance of approximately 4 mI/mm per 1.73 m2/yr re- disease (3 1) that probably affected our patients, even though gardless of gender. Apparently, there is no synergism between age this aspect was not investigated. and smoking; indeed, chronic smokers and ex-chronic smokers In conclusion, the present study demonstrates that cigarette had approximately I 00 and 80 mI/mm per 1.73 m2, respectively, smoking is associated with an impairment of renal function, less MAG1 clearance than age-matched controls at any age. Al- which seems irreversible, and possibly is mediated by a smok- though these effects of chronic cigarette smoking on renal func- ing-induced vasoactive hormone alteration. The precise signif- tion are reported here for the first time, the influence of age on icance of the MAG1 clearance anomaly, i.e., whether it mirrors renal blood flow and GFR is well known. It is generally accepted an abnormal renal blood flow or a tubulointerstitial derange- that the reduction in the number of functioning glomeruli, i.e., the ment, is unclear at present, and further investigations with expansion of glomerubosclerosis and renal atherosclerosis, ex- hippuran and/or Doppler sonography of the kidney are needed. plains the age effect on renal hemodynamics. However, the lost However, our study unequivocally shows that chronic smokers Renal Impairment in Chronic Cigarette Smokers 567
have a clear-cut abnormality in renal function. This point is comparison with Iodine-l23 and Iodine-l3l Orthoiodohippurate, important because the kidney has never been considered a in patients with renal disorders. J NucI Med 29: 147-158, 1988 casualty of smoke. The clinical implications of these smoking- 14. Nally JV, Chen C, Fine E, Fommei E, Ghione 5, Geyskes GO, related negative effects on the kidney are not clear; in panic- Hoffer PB, Sfakianakis 0: Diagnostic criteria for renovascular ular, it is uncertain whether smoking might determine or ag- hypertension with captopril renography: A consensus statement. Am J Hypertens 4: 7495-7525, 1991 gravate age-related changes in renal hemodynamics; critically 15. Blann AD, McCollum CN: Adverse influence ofcigarette smok- influence the outcome or natural history of nephropathies; or ing on the endothelium. Thromb Haemostasis 70: 707-7 1 1 , 1993 increase the vulnerability of the kidney to various noxae. Only 16. 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