Renal Impairment in Chronic Cigarette Smokers

Transcription

1 Renal Impairment in hroni igarette Smokers GIOVANNI GAMBARO,* FABIO VRLATO,t ALSSANDRO BUDAKOVI* DARIO ASARA, GIORGIO SALADINI, DORLLA DL PRT* GISLDA BRTAGLIA* MAURIZIO MASIRO,* SIMON HHTTO,* and BRUNO BAGGIO* *Jnstjtute of internal Mediine, Division of Nephrologv and NR enter on Aging, tangiology Seri ie, Nulear Mediine Servie, and entral Laboraton, University Hospital, Padua, Italy Abstrat To determine the effet of hroni igarette smoking on renal funtion, a rosssetional study was arried out with 30 subjets who had no known vasular disease risk fator other than igarette smoking, and 24 age and sexmathed ontrols without any vasular risk fator inluding igarette smoking Renal funtion by radionulide studies of renal plasma flow, GFR, and plasma endothelin 1 onentration was determined ompared with nonsmokers, smokers had a renal funtion impairment harateried by a normal GFR and a signifiant redution in renal plasma flow as refleted by MAG3 learane (19920 ± 5885 ml/min per 1 73 m2 versus ± 6014 mi/mm per 173 m2; t = 352, P < 0001) MAG1 learane was signifiantly orrelated with age and smoking The renal dysfuntion was assoiated with an inrease in plasma endothelinl onentration (2156 ± 115 pmolll versus 2501 ± 321 pmolll; t = 500, P < 0001) Former smokers as well had similar, although milder, abnormalities In onlusion, igarette smokers manifest an impairment of renal funtion, suggesting that smoke may have a detrimental effet on renal funtion (J Am So Nephrol 9: , 1998) igarette smoking is a major risk fator for vasular disease; it indues a variety of effets on the vasular and hormonal systems and is involved in the development of atheroslerosis, thrombogenesis, and vasular olusion ( I,2) The mehanisms of smokingrelated arterial damage have not yet been defined; however, a sympatheti stimulation, with onsequent release of the neurotransmitter norepinephrine (3), and morphologi and funtional endothebiab hanges, harateried by intimal smooth musle ell proliferation and alterations in endothelial prostaylin synthesis and endothelialderived vasular tone regulators (4), seem to play an important role Although the effet of smoking on peripheral vasular beds is well doumented, less information is available regarding its effet on the kidney A reent preliminary report suggests that smokingrelated hemodynami events may have an aute influene on renal funtion (5): other studies have proposed that smoking in diabetes mebbitus is assoiated with the development and/or progression of diabeti nephropathy (6) However, it is not known whether hroni smoking in itself has any adverse effet on renal funtion in a kidney not affeted by speifi diseases To address this issue, data were olleted from a rosssetional, linialbased investigation arried out at Padua Uni Reeived April Aepted Otober Preliminary data from this study were presented at the 33rd DTA/RA ongress Amsterdam June 1996, and published in abstrat form in Nephrol Dial Transplant I I : A72 I 996 orrespondene to Dr Bruno Baggio, Istituto di Mediina Interna, Polilinio Universitario via Giustiniani Padova, Italy b / $0300/() Journal of the Amerian Soiety of Nephrobogy opyright ( by the Amerian Soiety of Nephrobogy versity Hospital to evaluate the relationship between systemi atheroslerosis and renal funtion The findings obtained by analying renal funtion in a group of subjets who had no known vasular disease risk fator other than igarette smoking suggest that hroni igarette smoking has adverse renal effets Materials and Methods Patients The subjets who onstitute the basis of this study were reruited from among all of the patients older than age 55 referred to the angiology outpatient servie of Padua University Hospital from 1993 to 1995 Patients were referred to evaluate symptoms of possible atherosleroti origin (eg, general diiness, transient amaurosis, transient ishemi attak, intermittent laudiation), as well as for vein problems (eg, varies, thrombophbebitis) A total of 400 patients agreed to paniipate in a study projet to evaluate the assoiation between ardiovasular risk fators, peripheral vasular disease, and renal funtion Of these, only patients without laboratory evidene or personal history of nephropathy were onsidered Namely, in all reruited subjets, the serum reatinine level was < 136 jsmol/l, and urinalysis did not dislose hematuria, abnormal sediment, or proteinuria Proteinuria was ruled out on the basis of routine stix analysis (Mubtistix, Miles) negativity in two extemporary morning urine olletions performed on different days Furthermore, all available medial reords obtained from patients and from a searh of the files of this hospital were heked to exlude renal pathology Patients for whom it was not possible to obtain enough onfidene in ruling out previous renal pathology beause of the lak and/or unreliability of reords were not enrolled To exlude any interferene of renal hemodynamis, subjets on diureti, 3bboker, angiotensinonverting enyme inhibitor, or alium hannel bloker treatment were exluded Furthermore, beause the goal of the present study was to evaluate the role of smoking in kidney funtion, only those patients who had no or one ardiovasular risk fator, igarette smoking, were onsidered Therefore, patients

2 Renal Impairment in hroni igarette Smokers 563 with hyperlipemia (holesterol >60 mmolll and/or triglyerides > I 9 mmolfl), with systemi diseases predisposing to vasulitis or Raynaud s phenomenon, as well as subjets with BP repeatedly higher than 155/90 mmhg, were exluded This BP utoff is lower than that generally onsidered to define arterial hypertension (160/100 or I 60/95 mmhg) in the elderly and was hosen to improve our onfidene in exluding both systoli and systodiastoli hypertensive patients Also, subjets with diabetes or a family history of firstdegree relatives with diabetes were disarded No oral gluose tolerane test was performed, but all available medial reords of patients were heked, and fasting glyemia and glyosuria in two morning urine olletions were evaluated None had abnormal gluose values In summary, we enrolled 54 subjets: 24 nonsmokers onsidered as ontrols and 30 igarette smokers, of whih 1 3 were urrent smokers (> 10 igarettes/d sine young adult age) and 17 were former smokers who had quit smoking for 5 to 7 yr and were not exposed to passive smoking Aording to the study protool, the patients underwent a series of appropriate diagnosti proedures in the blind, inluding omplete physial evaluation and biohemial profile, ultrasonography with Doppler analysis for the loaliation of peripheral vasular disease, and renal funtion evaluation Body mass index was alulated Laboratory studies were performed in a fasting blood sample and inluded ell ount; hemoglobin onentration; prothrombin time and partial thromboplastin time: eletrolyte onentration; iron; total protein; protein eletrophoresis; bilirubin; alkaline phosphatase; transaminases; reatine phosphokinase; urea nitrogen; uri aid; reatinine; gluose; total, HDL, and LDL holesterol; and triglyerides On morning fresh urine, speifi gravity, ph, Multistix parameters, and the highpower field mirosopy of the sediment were exeuted Among these seleted patients, none had symptoms or personal history suggestive of oronary artery disease and all had a normal resting eletroardiogram Furthermore, none had a family history of premature vasular disease Atherosleroti lesions (ATS) in the arotid (7,8) and lower limb (9) arteries were sored as shown in Tables 1 and 2, respetively, and an ATS global sore (Table 3) was obtained in every subjet Aordingly, 16 of 30 igarette smokers and 8 of 24 nonsmokers had moderatetosevere peripheral atheroslerosis loaliation (ATS sore: 1 and 2, respetively), a differene that does not reah statistial signifiane Renal funtion was evaluated between 8 and 9 am, after at least 8 h of nonsmoking, by: (1) learane of tehnetium99mdiethylenetriamine pentaaeti aid (DTPA), whih is filtered only by the glomerulus, to measure GFR (10); and (2) learane of tehnetium99mmeraptoaetyltrigbyine (MAG3), whih was performed by the Bubek method (I I ) MAG1 is onsidered a valuable and suffiiently aurate probe in the linial setting for the noninvasive investigation of renal funtion Its ative transport by the renal tubular ell aounts for 89% of the total learane; the remaining portion is explained by glomerular filtration Although MAO3 is not as aurate as hippuran for estimating renal plasma flow (MAG3lhippuran learane ratio is approximately 060), the onversion of MAO3 learane values to Table 2 Atheroslerosis sore in lower limb arteries Atheroslerosis Involvement Stenosis Winsor s Index ATS Sore Nullmoderate <49% >09 0 Severe >50% <09 2 Table 3 Atheros lerosis global sore Atheroslerosis arotid ATS Lower Limb Artery Global ATS Involvement Sore ATS Sore Sorea Nullmild Moderate Severe a Defined aording to the most involved arterial distrit an equivalent hippuran learane, and therefore an equivalent renal plasma flow, was proposed beause the two learanes show a highly signifiant orrelation (r 095) (12,13) However, onsidering the pharmaokineti differenes that exist between the two agents, in agreement with most investigators we onsidered it more appropriate to ompare MAG1 learanes with normal values, rather than onvert them to a orresponding hippuran learane The sintigraphi tests were arried out 24 to 48 h apart; 200 MBq of the radiopharmaeutial (MAG3, Mallinkrodt Medial, Petten, Holland, and DTPA, SoboSorin, Saluggia, Italy) were prepared and standardied following the operating proedure inluded in the labeling kits before injetion Preparations with a radiohemial purity <97% were disarded Plasma endothelin 1 (T 1) onentration was also determined in blood samples drawn between 8 and 8:30 am The analysis was arried out in dupliate with an RIA kit (Peninsula Laboratories, Belmont, A) Results are expressed as the mean of the two determinations Statistial Anah ses Data are expressed as mean ± SD Statistial analysis was performed by t test for unpaired variables, oneway ANOVA, the Bonferroni test for subgroup omparisons, and by simple orrelation The relationship between MAG1 learane and GFR as dependent variables; other linial and demographi variables (ATS sore, atual or previous smoking habits, age, gender); and biohemial independent variables (serum levels of Tl total, HDL, and LDL holesterol; and triglyerides) were analyed by a stepdown multiple regression model omparisons of f3 oeffiients were performed with the t test Partial multiple orrelation was also arried out between MAO1 learane or GFR, age, and smoking (atual/former) Statistial signifiane was defined as a P value <005 Table 1 Atheroslerosis (ATS) sore in arotids Atheroslerosis Involvement Stenosis ATS Sore Nullmild 19% 0 Moderate >20 ± 49% 1 Severe 50 ± 74% 2 Very severe 75% 3 Results linial and biohemial parameters are summaried in Table 4 Smoker and nonsmoker groups were well mathed for a number of demographi, ardiovasular, and metaboli vanables In fat, average age; sex distribution; BP; body mass index; total, LDL, and HDL holesterol; and triglyeride blood levels were similar in both main groups and subgroups The parameters of the biohemial profile not shown in Table 1 were all in the normal range in all subjets

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4 Renal Impairment in hroni igarette Smokers 565 Aording to the riteria reported by Nally et al (14), no signifiant redution in perfusion indexes and/or asymmetry between the separate renogram profiles was observed in any subjet, whih thus exluded major renal vasular pathology In five subjets (three smokers, two nonsmokers) in whom sintigram findings were dubious, aptopnil sintigraphy ruled out major renovasular disease Although GFR did not differ between nonsmokers and smokers, the latter showed a signifiant redution in MAO1 learane (Table 4); no signifiant differene in these parameters was observed between former and urrent smokers To determine whether MAG1 learane and GFR levels were related to other linial and demographi fators besides smoking, stepdown multiple regression analysis was performed with MAG1 learane or GFR as dependent variables Age (3 = 489 ml/min per 173 m/yr, P = 0001), atual smoking ( ml/min per 1 73 m2/yr, P = 0000), and previous smoking (/3 = 6294 ml/min per 1 73 m2/yr, P = 0000) were the only statistially signifiant and independent variables influening the MAG1 learane (r = 078; F = 105; P = 0000) (Table 5) Moreover, the derease in MAG1 learane was lower in the former than in the urrent smokers I mi/mm per 173 m2/yr; t = 668; P = 0000) (Figure 1) The hypothesis of an interation between smoking and age was also tested, but it was not signifiant (/3 = 078 ml/min per 1 73 m2/yr; P = 079) The partial orrelation that was obtained onfirmed the signifiant inverse relationship between MAO1 learane and age (r = 053; P = 0000), and smoking (r = 069; P = 0000) Multiple regression analysis with GFR as the dependent variable did not give an adequate model (F = 1 08; r = 004; NS), but showed that only the relationship between GFR and age was signifiant (f3 = 1 55 ml/min per 1 73 m2/yr; P = 0020) (Table 6) The partial orrelation that was obtained onfirmed this relationship (r = 028; P = 0047) and further exludes a orrelation between GFR and smoking (r = 004; NS) When the subjets were subdivided into nonsmokers and O O A A A A U A #{149} so Age (years) Figure 1 Dispersion plot of meraptoaetyltriglyine (MAO3) learane values versus age Regression urves were obtained by multiple regression analyses (r = 071; F = 1441: P = 0000) The differene between partial regression oeffiient f3 is I 879 mb/mm per I 73 m2 (t = 668: P = 0000) U,, atual smokers; #{149},, former smokers; nonsmokers A A A A Table 6 Multivariate regression analysis of the relationship between GFR and other linial and demographi variables0 GFR, (mi/mm per 173 m) Partial Regression oeffiment (SM) Age (yr) 1 55 (064) 0020 PVabue Atual smoker ( 1 067) 0279(NS) Former smoker 273 ( 1060) 0799(NS) Gender 367 (960) 0703(NS) ATS (1016) 0657(NS) ATS (947) 0452(NS) Interept = 20098; F = 108; R2 = 013; P = 039 (NS) R = 036; a The analysis was arried out on 54 subjets (24 nonsmokers) Table 5 Multivaniate regression analysis of the relationship between MAO1 learane and other linial and demographi MAO1 learane (mllmin per 173 m2) vaniables#{176} Partial Regression Value oeffiient (SM) Age (yr) 489 (139) 0001 Atual smokers (1969) 0000 Former smokers 6294 (1947) 0000 Gender 874 (1758) 062l(NS) ATS (1956) 0080(NS) ATS (1828) 0296(NS) Interept = 6181; F = 105; R2 = 061; R = 078; P = 0000 a The analysis was arried out on 54 subjets (24 nonsmokers) and is the result of a stepdown multiple regression by exluding the less signifiant variables smokers, and the data analyed by simple orrelation, the same trend was observed only in the nonsmokers (r = 056; P = 0004), whereas the relationship disappeared in the smokers (r 011; NS) Finally, ompared with nonsmokers, smokers showed a higher plasma T 1 onentration In an attempt to improve the models to desribe MAG1 learane and GFR, multiple regression analysis was performed adding T 1 to the previous independent variables (gender, age, smoking habits, ATS sore), as well as serum levels of total, HDL, and LDL holesterol, and triglyerides onerning MAG1, the derived model was improved (F = 227; P = 00000; r = 083; r 069) and revealed that MAO1 learane is influened by T 1 as well (P = 00001), whereas the other metaboli variables were not signifiantly orrelated On the ontrary, the model of GFR was not improved, and namely T 1 was not a statistially signifiant determinant

5 566 Journal of the Amerian Soiety of Nephrobogy Disussion The present study demonstrates that hroni igarette smokens have a renal funtion impairment harateried by a normal GFR and a signifiant redution in renal plasma flow as evidened by MAG1 learane The possibility that a seletion bias ould explain the present results seems unlikely Although we onsidered only subjets admitted to an angiology servie (ie, who might not orrespond to the general, but rather to an atherosleroti population), many of these patients were referred for trivial vasular symptoms that only hypothetially were atherosleroti in origin; indeed, only 24 of 54 patients showed a moderate or severe peripheral atheroslerosis on ultrasonography and Doppler analysis Therefore, the study subjets onstitute a mixed group, whih might resemble the general, >55yrold population Furthermore, smoker and nonsmoker groups were well mathed for a number of demographi, ardiovasular, and metaboli variables In fat, average age; sex distribution; BP; body mass index; total, LDL, and HDL holesterol: and triglyeride blood levels were similar in both main groups and subgroups: Moreover, the global ATS sore did not orrelate with renal funtion These findings argue against bias introdued from preexisting vasular disease Until now, investigators and liniians essentially have foused on the role of ative and passive smoking as a risk fator for arterial damage, a risk fator whose magnitude is omparable to the other well known vasular risk fators: hypertension and hyperholesterolemia Indeed, smoking is strongly assoiated with oronary, erebral, and peripheral vasular disease ( 1,2) This is the first report showing an adverse effet of hroni smoking on kidney funtion In fat, only a few studies have addressed the aute effet of smoke on renal funtion (5) and the possible aggravating risk of smoke on diabeti nephropathy (6) The renal dysfuntion was also observed in subjets who quit smoking, suggesting that funtional, initially reversible hanges probably beame fixed after years of smoking This observation, the 8h washout from smoking before performing learane studies, and, finally, evidene that a number of smokeindued aute phenomena are shorter, ie, the endothehal release of the von Willebrand fator ( 15) and of T 1 ( 16), do not support the idea that the renal alteration observed in atual smokers might be due to an aute smoke effet The MAG1 learane values were statistially explained by linial and demographi fators: age and smoking habits In the age range onsidered (55 to 85 yr), subjets showed a redution in MAG1 learane of approximately 4 mi/mm per 1 73 m2/yr regardless of gender Apparently, there is no synergism between age and smoking; indeed, hroni smokers and exhroni smokers had approximately I 00 and 80 mi/mm per 173 m2, respetively, less MAG1 learane than agemathed ontrols at any age Although these effets of hroni igarette smoking on renal funtion are reported here for the first time, the influene of age on renal blood flow and GFR is well known It is generally aepted that the redution in the number of funtioning glomeruli, ie, the expansion of glomeruboslerosis and renal atheroslerosis, explains the age effet on renal hemodynamis However, the lost relationship between GFR and age in our smokers suggests that the mehanism of the smoking effet on renal funtion is different from that of the agerelated one The hemodynami renal profile of smokers is similar to that observed in hypertensive arteriolar nephroslerosis, in whih the earliest impairment in overall renal funtion is a redution in renal plasma flow and a usually normal GFR (17) However, beause none of the smoking subjets was hypertensive and mean arterial pressure was not different among groups, we believe that the alteration we desribe is really a smokerelated dysfuntion An attempt was made to dislose pathophysiologi mehanisms responsible for the renal alteration in smokers A number of irulating and loal vasoative fators were found to be altered in smoking subjets, whih might play a role in the smokeassoiated effet on renal flow (3,1824) Among these, T 1 is very interesting It is known that T 1 is an important mediator of pathophysiologi alterations in renal hemodynamis It is a very powerful vasopressor agent, fivefold more potent than angiotensin ating on both afferent and efferent arterioles In rats, Tl infusion onstrits the efferent more than the afferent arteriole, with an attendant inrease in glomerular apillary pressure and a derease in the ultrafiltration oeffiient (25,26) In dogs, Tl redues renal blood flow and inreases renal vasular resistane, without produing any signifiant modifiation of glomerular filtration at pathophysiologi onentrations (27) Furthermore, Tl has potent mitogeni and atherogeni ativities on vasular smooth musle and mesangial ells (28) Thus, Tl might explain the full piture of renal hanges observed in ative and former smoking subjets, ie, both funtional (present data) and morphopathologi alterations (renal arteriolar thikening) reported by previous autopsy studies (29,30) Indeed, the plasma onentration of Tl was reported to be inreased in smokers (24), and our study, showing higher plasma values of T1 in smokers and, in paniular, in the atual smokers, onfirms this Furthermore, T 1 emerged as a signifiant determinant of MAG1 learane This finding strongly supports the hypothesis that Tl has a signifiant role in smokeassoiated renal impairment Although arbon monoxideindued hypoxia, niotineindued a 1 adrenergi stimulation, and oxygenfree radials may all onur to explain the inreased plasma level of endothelin in urrent smokers (28), the inrease in Tl observed in former smokers might be seondary to the irreversible renal vasular damage desribed in igarette smokers (29,30), or to a subtle hypoxia due to mild hroni obstrutive pulmonary disease (3 1) that probably affeted our patients, even though this aspet was not investigated In onlusion, the present study demonstrates that igarette smoking is assoiated with an impairment of renal funtion, whih seems irreversible, and possibly is mediated by a smokingindued vasoative hormone alteration The preise signifiane of the MAG1 learane anomaly, ie, whether it mirrors an abnormal renal blood flow or a tubulointerstitial derangement, is unlear at present, and further investigations with hippuran and/or Doppler sonography of the kidney are needed However, our study unequivoally shows that hroni smokers

6 Renal Impairment in hroni igarette Smokers 567 have a learut abnormality in renal funtion This point is important beause the kidney has never been onsidered a asualty of smoke The linial impliations of these smokingrelated negative effets on the kidney are not lear; in paniular, it is unertain whether smoking might determine or aggravate agerelated hanges in renal hemodynamis; ritially influene the outome or natural history of nephropathies; or inrease the vulnerability of the kidney to various noxae Only epidemiologi and followup investigations will larify these negleted issues; however, it is noteworthy that in diabetes, smoking is an important risk fator for the onset and evolution of nephropathy (6) Aknowledgment This study was supported by a grant from the National Researh ommittee, Rome (PF INV, 94XXX) entro per lo Studio dello lnvehiamento, Padova Referenes 1 Report of the Surgeon General: The health onsequenes of smoking: ardiovasular disease Washington D, US Department of 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