Authors' reply:

Abstract

Remuzzi has commented on our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar raising some interesting points: the similarity of our renal findings in cigarette smokers with the hemodynamic effects of cyclosporine, and the role of endothelin(s) in the physiopathology of such smoke-induced renal alterations. We gratefully acknowledge his contribution and the opportunity the American Journal of Kidney Diseases gives to us to clarify some aspects of our paper and to introduce potentially interesting and logical inferences from its findings.First of all, let us consider the similarity of our observations in cigarette smokers to the hemodynamic effects of cyclosporine. The papers cited by Remuzzi show that the acute administration of cyclosporine has a detrimental effect on both the glomerular filtration rate (GFR) and renal plasma flow (RPF), whereas in a chronic condition no statistical significant effect was observed.2Ruggenenti P Perico N Amuchastegui GS Ferrazzi P Mamprin F Remuzzi G Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine.Am J Kidney Dis. 1994; 24: 549-553Abstract Full Text PDF PubMed Scopus (32) Google Scholar However, this is not what we observed in chronic cigarette smokers, because only a reduction of RPF was noted. Furthermore, the acute studies available so far make no contribution to a matching of cyclosporine with smoke “nephrotoxicity.” Franek et al3Franek E Benk U Reinbold F Fliser D Clorius J Ritz E Acute influence of smoking on renal function.Nephrol Dial Transplant. 1996; 11 (abstr): 65ACrossref PubMed Scopus (8) Google Scholar showed that cigarette smoke induces a reduction of GFR (determined with 99mtechnetium-diethylenetriamine pentaacetic acid (DTPA), as in our case), but not of RPF (determined with hippurate, whereas we used 99mtechnetium-mercaptoacetyltriglycine [MAG3 ]). Halimi et al,4Halimi J-M Philippon C Mimran A Contrasting renal effects of nicotine in smokers and non-smokers.Nephrol Dial Transplant. 1998; 13: 940-944Crossref PubMed Scopus (68) Google Scholar using the same radiotracers as Franek et al,3Franek E Benk U Reinbold F Fliser D Clorius J Ritz E Acute influence of smoking on renal function.Nephrol Dial Transplant. 1996; 11 (abstr): 65ACrossref PubMed Scopus (8) Google Scholar after the acute administration of nicotine, observed a reduction of both GFR and RPF in nonsmokers and no renal effect in chronic smokers. The available studies thus give results somehow in contrast with the acute renal effect of cyclosporine and support the opinion that the experimental conditions used (acute v chronic) and specific chemical component of the cigarette smoke may be very important.We also have some doubt regarding the interpretation of results obtained from the determination of RPF by clearance studies. Theory requires that the ideal probe to be used for such a goal be freely filtered by the glomerulus and completely extracted by the tubule. This implies that the tubulointerstitial compartment (we prefer to refer to this integrated structure rather than to the tubule alone because of the anatomo-functional connection between the two anatomic structures) has to be normal. We have no idea of the status of the tubulointerstitium in chronic cigarette smokers, but our feeling is that probably it is not normal. This doubt has nothing to do with the kind of probe used to evaluate RPF. As we stated in our paper, it is true that MAG3 is not as accurate as hippuran for estimating RPF; however, both need to be actively extracted by the tubular epithelium from the blood, and thus both clearances are potentially biased by tubulointerstitial damage.For these reasons, we think that before deducing definite renal hemodynamic damage induced by smoking, more accurate investigations using direct methods to evaluate the renal flow are necessary, because the same results also could be the consequence of a tubulointerstitial involvement.However, we certainly agree with Remuzzi that the functional findings we observed in chronic cigarette smokers are, as with cyclosporine, most probably related to structural alterations of small renal vessels—as already reported.5Black HR Zeevi GR Silten RM Smith GJW Effect of heavy cigarette smoking on renal and myocardial arterioles.Nephron. 1983; 34: 173-179Crossref PubMed Scopus (59) Google Scholar, 6Oberai B Adams CWM High OB Myocardial and renal arteriolar thickening in cigarette smoking.Atherosclerosis. 1984; 52: 185-190Abstract Full Text PDF PubMed Scopus (35) Google Scholar There is no reason to think that the renal vasculature is protected from the atherogenic effect of smoke, as distinct from other parenchyma, and the tubulointerstitial damage we hypothesize in itself might be due to an altered renal perfusion.In this regard, the similarity between the renal “hemodynamic” (we use this term for simplicity) profile observed in cigarette smokers and that seen in hypertensive arteriolar nephrosclerosis is quite interesting in view of the still-debated issue of the relationship between so-called nephro(angio)sclerosis, which is generally thought to be caused by hypertension, and end-stage renal disease.7Zucchelli P Zuccalà A Hypertension and renal dysfunction.Curr Opin Nephrol Hypertens. 1996; 5: 97-101Crossref PubMed Scopus (13) Google Scholar The paradox of a relentless increase in hypertensive end-stage renal disease rates, despite the concurrent improvement in hypertension control and the substantial reduction in other hypertension-related events, could be attributable to the fact that nephro(angio)sclerosis has causes other than hypertension, such as (one can speculate) cigarette smoking, which may or may not coexist with hypertension. We have data supporting this idea,8Budakovic A Gambaro G Del Prete D Verlato F Casara D Saladini G Baggio B Renal function in subjects with peripheral atherosclerosis.Nephrol Dial Transplant. 1998; 13 (abstr): 136AGoogle Scholar and accordingly, we speculate that the renal “hemodynamic” profile observed in smokers constitutes functional evidence of the silent phase of ischemic renal disease. This interpretation agrees with the suggestion of Zucchelli and Zuccalà that renal ischemia also may be caused by damage to the small intraparenchymal arteries and arterioles.9Zucchelli P Zuccalà A Ischemic nephropathy in the elderly.Contrib Nephrol. 1993; 105: 13-24PubMed Google ScholarIt is also interesting to consider the findings of the effect of chronic smoking on renal function regarding the problem of the physiological loss of renal function with senescence. This is no longer an axiom, as clearly shown by the Baltimore Longitudinal Study of Aging and the Bronx Longitudinal Aging Study.10Lindeman RD Tobin J Shock NW Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc. 1985; 33: 278-285Crossref PubMed Scopus (1223) Google Scholar, 11Feinfeld DA Guzik H Carvounis CP Lynn RI Somer B Aronson MK Frishman WH Sequential changes in renal function tests in the old: Results from the Bronx longitudinal study.J Am Geriatr Soc. 1995; 43: 412-414Crossref PubMed Scopus (19) Google Scholar The reasons for the inconstant loss of renal function with aging are unclear, but it is probably that comorbid conditions added to age play a role. Evidence exists to support the opinion that among them cardiovascular risk factors have to be included, such as hypertension, diabetes, hyperlipidemia, but possibly, as suggested by our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar also cigarette smoking.Let us now consider the second point, that is, the role of endothelin(s) in the pathogenesis of the functional alteration in smokers. Here, our attention was focused on endothelin(s) because, as we stated in our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar this might explain the picture of renal changes observed in smokers that is, both functional and morphopathological alterations (renal arteriolar thickening). We agree with many of the interesting comments put forward by Remuzzi. Certainly, the modest increase in plasma endothelin-1 observed in smokers hardly has a direct functional role in the kidney. However, we believe this simply mirrors increased local (in the kidney and other tissue vasculature) levels of endothelin-1, which certainly are extremely important in functional terms regarding vascular tone and because of their paracrine activity.We agree that a number of circulating and local vasoactive factors could be involved in causing the renal functional alterations observed in smokers. However, we believe that among the potential mechanisms of smoking-induced renal damage, the atherogenic effects of smoke should be taken into account, for instance, because of its unfavorable effect on lipoprotein and glycosaminoglycan (GAG) metabolism.Epidemiological studies have indicated that cigarette smoking is associated with a change in plasma lipoprotein and fatty acid levels, and that the atherosclerotic risk related to smoking is partially attributable to its influence on lipoproteins. Smoking, through sympathetic system-nicotine stimulation, induces increased plasma concentrations of low-density lipoproteins (LDL) and triglycerides, and a decrease in high-density lipoproteins.12Brischetto CS Connor WE Connor SL Matarazzo JD Plasma lipid and lipoprotein profiles of cigarette smokers from randomly selected families: Enhancement of hyperlipidemia and depression of high-density lipoprotein.Am J Cardiol. 1983; 52: 675-680Abstract Full Text PDF PubMed Scopus (105) Google Scholar Moreover, smoking causes oxidative modifications of biological components, including LDL. Oxidative modifications of the latter are thought to be a key process in the development of atherosclerosis; indeed, it has been shown that oxidatively modified LDL is recognized by scavenger receptors and taken up by macrophages, a process considered pivotal in the development of foam cells in atherosclerotic lesions.13Parthasarathy S Steinberg D Witztum JL The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis.Annu Rev Med. 1992; 43: 219-225Crossref PubMed Scopus (368) Google ScholarConversely, we should not forget the adverse effect of smoke on GAGs, in particular the alteration of their anion charge density14Humphries DE Lee SL Fanburg BL Silbert JE Effects of hypoxia and hyperoxia on proteoglycan production by bovine pulmonary artery endothelial cells.J Cell Physiol. 1986; 126: 249-253Crossref PubMed Scopus (27) Google Scholar, 15Kashihara N Watanabe Y Makino H Wallner EI Kanwar Y Selective decrease of de novo synthesis of glomerular proteoglycans under the influence of reactive oxygen species.Proc Natl Acad Sci U S A. 1993; 89: 6309-6313Crossref Scopus (70) Google Scholar; GAGs are the main constituent of the arterial wall, where they are synthesized by endothelial and smooth muscle cells.16Schmidt A Bunte A Buddecke E Proliferation-dependent changes of proteoglycan metabolism in arterial smooth muscle cells.Biol Chem Hoppe-Seyler. 1987; 368: 277-284Crossref PubMed Scopus (15) Google Scholar These molecules are involved in a number of biological processes and seem to play an important role in the pathogenesis of atherosclerosis through their ability to interact with lipoproteins17Camejo G Acquatella H Lalaguna F The interaction of low density lipoproteins with arterial proteoglycan: An additional risk factor.Atherosclerosis. 1980; 36: 55-65Abstract Full Text PDF PubMed Scopus (40) Google Scholar; these complexes cause the accumulation of LDL in the arterial wall and the subsequent development of atherosclerotic lesions. Moreover, GAGs may influence the adhesion, migration, and proliferation of macrophages, endothelial, and smooth muscle cells, which are all events known to be crucial in the pathogenesis of atherosclerosis.18Ziad A Keane M Keane WF Pathogenesis of atherosclerosis.Semin Nephrol. 1996; 16: 12-20PubMed Google ScholarThe similarity between pathobiological mechanisms in atherosclerosis and glomerulosclerosis, and the possibility that atherosclerosis degenerative lesions also of the small interstitial vasculature in the kidney have a role in explaining our findings, all support our emphasis on the above mechanisms. Remuzzi has commented on our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar raising some interesting points: the similarity of our renal findings in cigarette smokers with the hemodynamic effects of cyclosporine, and the role of endothelin(s) in the physiopathology of such smoke-induced renal alterations. We gratefully acknowledge his contribution and the opportunity the American Journal of Kidney Diseases gives to us to clarify some aspects of our paper and to introduce potentially interesting and logical inferences from its findings. First of all, let us consider the similarity of our observations in cigarette smokers to the hemodynamic effects of cyclosporine. The papers cited by Remuzzi show that the acute administration of cyclosporine has a detrimental effect on both the glomerular filtration rate (GFR) and renal plasma flow (RPF), whereas in a chronic condition no statistical significant effect was observed.2Ruggenenti P Perico N Amuchastegui GS Ferrazzi P Mamprin F Remuzzi G Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine.Am J Kidney Dis. 1994; 24: 549-553Abstract Full Text PDF PubMed Scopus (32) Google Scholar However, this is not what we observed in chronic cigarette smokers, because only a reduction of RPF was noted. Furthermore, the acute studies available so far make no contribution to a matching of cyclosporine with smoke “nephrotoxicity.” Franek et al3Franek E Benk U Reinbold F Fliser D Clorius J Ritz E Acute influence of smoking on renal function.Nephrol Dial Transplant. 1996; 11 (abstr): 65ACrossref PubMed Scopus (8) Google Scholar showed that cigarette smoke induces a reduction of GFR (determined with 99mtechnetium-diethylenetriamine pentaacetic acid (DTPA), as in our case), but not of RPF (determined with hippurate, whereas we used 99mtechnetium-mercaptoacetyltriglycine [MAG3 ]). Halimi et al,4Halimi J-M Philippon C Mimran A Contrasting renal effects of nicotine in smokers and non-smokers.Nephrol Dial Transplant. 1998; 13: 940-944Crossref PubMed Scopus (68) Google Scholar using the same radiotracers as Franek et al,3Franek E Benk U Reinbold F Fliser D Clorius J Ritz E Acute influence of smoking on renal function.Nephrol Dial Transplant. 1996; 11 (abstr): 65ACrossref PubMed Scopus (8) Google Scholar after the acute administration of nicotine, observed a reduction of both GFR and RPF in nonsmokers and no renal effect in chronic smokers. The available studies thus give results somehow in contrast with the acute renal effect of cyclosporine and support the opinion that the experimental conditions used (acute v chronic) and specific chemical component of the cigarette smoke may be very important. We also have some doubt regarding the interpretation of results obtained from the determination of RPF by clearance studies. Theory requires that the ideal probe to be used for such a goal be freely filtered by the glomerulus and completely extracted by the tubule. This implies that the tubulointerstitial compartment (we prefer to refer to this integrated structure rather than to the tubule alone because of the anatomo-functional connection between the two anatomic structures) has to be normal. We have no idea of the status of the tubulointerstitium in chronic cigarette smokers, but our feeling is that probably it is not normal. This doubt has nothing to do with the kind of probe used to evaluate RPF. As we stated in our paper, it is true that MAG3 is not as accurate as hippuran for estimating RPF; however, both need to be actively extracted by the tubular epithelium from the blood, and thus both clearances are potentially biased by tubulointerstitial damage. For these reasons, we think that before deducing definite renal hemodynamic damage induced by smoking, more accurate investigations using direct methods to evaluate the renal flow are necessary, because the same results also could be the consequence of a tubulointerstitial involvement. However, we certainly agree with Remuzzi that the functional findings we observed in chronic cigarette smokers are, as with cyclosporine, most probably related to structural alterations of small renal vessels—as already reported.5Black HR Zeevi GR Silten RM Smith GJW Effect of heavy cigarette smoking on renal and myocardial arterioles.Nephron. 1983; 34: 173-179Crossref PubMed Scopus (59) Google Scholar, 6Oberai B Adams CWM High OB Myocardial and renal arteriolar thickening in cigarette smoking.Atherosclerosis. 1984; 52: 185-190Abstract Full Text PDF PubMed Scopus (35) Google Scholar There is no reason to think that the renal vasculature is protected from the atherogenic effect of smoke, as distinct from other parenchyma, and the tubulointerstitial damage we hypothesize in itself might be due to an altered renal perfusion. In this regard, the similarity between the renal “hemodynamic” (we use this term for simplicity) profile observed in cigarette smokers and that seen in hypertensive arteriolar nephrosclerosis is quite interesting in view of the still-debated issue of the relationship between so-called nephro(angio)sclerosis, which is generally thought to be caused by hypertension, and end-stage renal disease.7Zucchelli P Zuccalà A Hypertension and renal dysfunction.Curr Opin Nephrol Hypertens. 1996; 5: 97-101Crossref PubMed Scopus (13) Google Scholar The paradox of a relentless increase in hypertensive end-stage renal disease rates, despite the concurrent improvement in hypertension control and the substantial reduction in other hypertension-related events, could be attributable to the fact that nephro(angio)sclerosis has causes other than hypertension, such as (one can speculate) cigarette smoking, which may or may not coexist with hypertension. We have data supporting this idea,8Budakovic A Gambaro G Del Prete D Verlato F Casara D Saladini G Baggio B Renal function in subjects with peripheral atherosclerosis.Nephrol Dial Transplant. 1998; 13 (abstr): 136AGoogle Scholar and accordingly, we speculate that the renal “hemodynamic” profile observed in smokers constitutes functional evidence of the silent phase of ischemic renal disease. This interpretation agrees with the suggestion of Zucchelli and Zuccalà that renal ischemia also may be caused by damage to the small intraparenchymal arteries and arterioles.9Zucchelli P Zuccalà A Ischemic nephropathy in the elderly.Contrib Nephrol. 1993; 105: 13-24PubMed Google Scholar It is also interesting to consider the findings of the effect of chronic smoking on renal function regarding the problem of the physiological loss of renal function with senescence. This is no longer an axiom, as clearly shown by the Baltimore Longitudinal Study of Aging and the Bronx Longitudinal Aging Study.10Lindeman RD Tobin J Shock NW Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc. 1985; 33: 278-285Crossref PubMed Scopus (1223) Google Scholar, 11Feinfeld DA Guzik H Carvounis CP Lynn RI Somer B Aronson MK Frishman WH Sequential changes in renal function tests in the old: Results from the Bronx longitudinal study.J Am Geriatr Soc. 1995; 43: 412-414Crossref PubMed Scopus (19) Google Scholar The reasons for the inconstant loss of renal function with aging are unclear, but it is probably that comorbid conditions added to age play a role. Evidence exists to support the opinion that among them cardiovascular risk factors have to be included, such as hypertension, diabetes, hyperlipidemia, but possibly, as suggested by our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar also cigarette smoking. Let us now consider the second point, that is, the role of endothelin(s) in the pathogenesis of the functional alteration in smokers. Here, our attention was focused on endothelin(s) because, as we stated in our paper,1Gambaro G Verlato F Budakovic A Casara D Saladini G Del Prete D Bertaglia G Masiero M Checchetto S Baggio B Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar this might explain the picture of renal changes observed in smokers that is, both functional and morphopathological alterations (renal arteriolar thickening). We agree with many of the interesting comments put forward by Remuzzi. Certainly, the modest increase in plasma endothelin-1 observed in smokers hardly has a direct functional role in the kidney. However, we believe this simply mirrors increased local (in the kidney and other tissue vasculature) levels of endothelin-1, which certainly are extremely important in functional terms regarding vascular tone and because of their paracrine activity. We agree that a number of circulating and local vasoactive factors could be involved in causing the renal functional alterations observed in smokers. However, we believe that among the potential mechanisms of smoking-induced renal damage, the atherogenic effects of smoke should be taken into account, for instance, because of its unfavorable effect on lipoprotein and glycosaminoglycan (GAG) metabolism. Epidemiological studies have indicated that cigarette smoking is associated with a change in plasma lipoprotein and fatty acid levels, and that the atherosclerotic risk related to smoking is partially attributable to its influence on lipoproteins. Smoking, through sympathetic system-nicotine stimulation, induces increased plasma concentrations of low-density lipoproteins (LDL) and triglycerides, and a decrease in high-density lipoproteins.12Brischetto CS Connor WE Connor SL Matarazzo JD Plasma lipid and lipoprotein profiles of cigarette smokers from randomly selected families: Enhancement of hyperlipidemia and depression of high-density lipoprotein.Am J Cardiol. 1983; 52: 675-680Abstract Full Text PDF PubMed Scopus (105) Google Scholar Moreover, smoking causes oxidative modifications of biological components, including LDL. Oxidative modifications of the latter are thought to be a key process in the development of atherosclerosis; indeed, it has been shown that oxidatively modified LDL is recognized by scavenger receptors and taken up by macrophages, a process considered pivotal in the development of foam cells in atherosclerotic lesions.13Parthasarathy S Steinberg D Witztum JL The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis.Annu Rev Med. 1992; 43: 219-225Crossref PubMed Scopus (368) Google Scholar Conversely, we should not forget the adverse effect of smoke on GAGs, in particular the alteration of their anion charge density14Humphries DE Lee SL Fanburg BL Silbert JE Effects of hypoxia and hyperoxia on proteoglycan production by bovine pulmonary artery endothelial cells.J Cell Physiol. 1986; 126: 249-253Crossref PubMed Scopus (27) Google Scholar, 15Kashihara N Watanabe Y Makino H Wallner EI Kanwar Y Selective decrease of de novo synthesis of glomerular proteoglycans under the influence of reactive oxygen species.Proc Natl Acad Sci U S A. 1993; 89: 6309-6313Crossref Scopus (70) Google Scholar; GAGs are the main constituent of the arterial wall, where they are synthesized by endothelial and smooth muscle cells.16Schmidt A Bunte A Buddecke E Proliferation-dependent changes of proteoglycan metabolism in arterial smooth muscle cells.Biol Chem Hoppe-Seyler. 1987; 368: 277-284Crossref PubMed Scopus (15) Google Scholar These molecules are involved in a number of biological processes and seem to play an important role in the pathogenesis of atherosclerosis through their ability to interact with lipoproteins17Camejo G Acquatella H Lalaguna F The interaction of low density lipoproteins with arterial proteoglycan: An additional risk factor.Atherosclerosis. 1980; 36: 55-65Abstract Full Text PDF PubMed Scopus (40) Google Scholar; these complexes cause the accumulation of LDL in the arterial wall and the subsequent development of atherosclerotic lesions. Moreover, GAGs may influence the adhesion, migration, and proliferation of macrophages, endothelial, and smooth muscle cells, which are all events known to be crucial in the pathogenesis of atherosclerosis.18Ziad A Keane M Keane WF Pathogenesis of atherosclerosis.Semin Nephrol. 1996; 16: 12-20PubMed Google Scholar The similarity between pathobiological mechanisms in atherosclerosis and glomerulosclerosis, and the possibility that atherosclerosis degenerative lesions also of the small interstitial vasculature in the kidney have a role in explaining our findings, all support our emphasis on the above mechanisms.