Kidney International, Vol. 61 (2002), pp. 648–654

Cigarette smoking and vascular pathology in renal biopsies

KARL LHOTTA, HANS J. RUMPELT, PAUL KONIG, GERT MAYER, and FLORIAN KRONENBERG

Clinical Nephrology Division, Department of Internal Medicine, Innsbruck University Hospital, Innsbruck, Austria; Instituteof Pathology, Heilbronn Hospital, Heilbronn, Germany; and Institute of Medical Biology and Human Genetics, Universityof Innsbruck, Innsbruck, Austria

Cigarette smoking and vascular pathology in renal biopsies. ulation [1, 2]. In recent years smoking has been pin-Background. In recent years cigarette smoking has been pointed as a progression factor for chronic nephropa-

identified as a progression factor in chronic nephropathies such thies. Tobacco abuse is highly associated with clinicallyas glomerulonephritis or diabetic nephropathy. The exact pa-important reduction in renal function in elderly peoplethomechanism of nicotine-induced renal damage is, however,[3] and with albuminuria in patients with hypertensionunknown. Autopsy studies and functional investigations sug-

gest that the renal vasculature is primarily affected by smoking. [4]. The Multiple Risk Factor Intervention Trial foundMethods. Renal vascular pathology, that is, glomeruloscle- smoking to be a significant risk factor for end-stage re-

rosis, hyalinosis of arterioles and myointimal hyperplasia ofnal disease (abstract; Whelton et al, J Am Soc Nephrolsmall arteries, was determined in 135 biopsies of patients over6:408a, 1995). In patients with kidney disease, smokingthirty years of age. A questionnaire about smoking habits was

returned by 107 of the patients. For glomerular sclerosis the is associated with elevated serum creatinine levels inpercentage of sclerotic glomeruli was determined, whereas ar- chronic glomerulonephritis [5] and speeds up loss of glo-teriolar hyalinosis and myointimal hyperplasia of small arteries merular filtration in lupus nephritis [6] and diabetic ne-were described as present or absent without further quantifica-

phropathy in type I and type II diabetes [7–9]. In patientstion. A univariate analysis was performed for existence of vas-with autosomal dominant polycystic kidney disease andcular changes and ever-smoking status. In addition, a multivari-

ate analysis for glomerular sclerosis and logistic regression IgA nephropathy nicotine abuse increases the risk ofanalysis for arteriolar hyalinosis and myointimal hyperplasia end-stage renal disease [10].and the variables ever-smoking, age, body mass index, creati-

Despite these clinical data the mechanism by whichnine clearance, blood pressure and lipids were performed.smoking and nicotine exert their deleterious effects onResults. Creatinine clearance was comparable for nonsmok-

ers, ex-smokers and smokers. Frequency of myointimal hyper- a predamaged kidney are largely unknown. Autopsyplasia of small arteries was twice as high in ever-smokers as studies in individuals without kidney disease showed acompared to nonsmokers (50% vs. 25.5%, P � 0.01). Arteriolar correlation between nicotine abuse and thickening ofhyalinosis was detected in 23.5% of nonsmokers and in 35.7%

the walls of arterioles and small arteries in various organsof smokers, showing a trend toward hyalinosis in ever-smokers[11] and the kidneys [12, 13]. At present, it is not known(P � 0.20). Glomerular sclerosis was found in 62.7% of non-

smokers and in 69.6% of ever-smokers. Logistic regression whether analogous effects of smoking on renal vesselsanalysis confirmed an association between ever-smoking and are operative in patients with chronic nephropathies ormyointimal hyperplasia (P � 0.01). This association also was whether they might be the cause of accelerated deterio-present in males and patients over fifty years of age, but not

ration of renal function in smokers suffering from kidneyin younger patients and females.disease. To shed some light on this problem we investi-Conclusion. In patients with renal, especially glomerular dis-

ease, cigarette smoking exhibits its deleterious effect on the gated damage of renal vessels, defined as sclerosis ofkidneys primarily through damage of small interlobular arteries. glomerular capillaries, hyalinosis of arterioles and myo-

intimal hyperplasia of interlobular arteries, in kidneybiopsies and correlated these findings with the smoking

Cigarette smoking is an established risk factor for car- habit of the patients.diovascular disease and malignancies in the general pop-

METHODSKey words: glomerulonephritis, glomerulosclerosis, arterioles, nico-

Patientstine, renal vasculature, progressive renal disease, hypertension.

All 567 patients undergoing a kidney biopsy at ourReceived for publication May 22, 2001

institution between 1990 and 2000 were considered forand in revised form September 25, 2001Accepted for publication September 26, 2001 further investigation. The following inclusion criteria

were applied: age over 30 years at time of biopsy; at 2002 by the International Society of Nephrology

648

Lhotta et al: Smoking and renal vascular pathology 649

Table 2. Histological diagnosis of renal biopsiesTable 1. Characterization of patients

Variable Diagnosis Number of cases (107)

Focal segmental glomerulosclerosis 18Age 48�12 [47 (30-74)]Body mass index 25.4�4.3 IgA nephropathy 20

Membranous nephropathy 15Creatinine clearance mL/min 67�37 [67 (6-168)]Proteinuria g/24 h 4.3�4.4 [2.8 (0.1-26.5)] Rapidly progressive glomerulonephritis 9

Minimal change nephropathy 8Systolic RR mm Hg 152�27Diastolic RR mm Hg 91�14 Nephrosclerosis 8

Membranoproliferative glomerulonephritis 6Serum cholesterol mg/dL 242�82HDL cholesterol mg/dL 51�21 Mesangial glomerulonephritis 6

Lupus nephritis 5LDL cholesterol mg/dL 157�76Serum triglycerides mg/dL 177�87 [171 (49-544)] Chronic interstitial nephritis 3

Acute interstitial nephritis 2Values are presented as mean � SD and as [median (range)] where appro-Alport syndrome 2priate.Thin basement membranes 1Light chain nephropathy 1Diabetic nephropathy 1Renal fibrosis 1Normal kidney 1least three glomeruli and one section of an interlobular

artery as well as arterioles had to be present in the tissuespecimen of each biopsy. These criteria were met in 135cases. The absence of an interlobular artery was by far

Any glomerulus showing segmental or complete sclerosisthe most frequent exclusion criterion.was classified as affected by glomerular capillary sclero-sis. The percentage of affected glomeruli was calculatedAssessment of smoking habitsfor each biopsy. The number of arterioles was assessed

We sent each patient a letter explaining the purposein each biopsy. Due to the smaller numbers of arterioles,

of the study and a questionnaire about smoking habits.any biopsy showing hyalinosis in at least one arteriole

The letter included a statement saying that by replying was classified positive for the presence of hyalinosis.to the questionnaire the patient would not incur any Likewise, the number of interlobular arteries was deter-disadvantage whatsoever. The return sheet was anony- mined, and any case showing myointimal hyperplasia inmous and allowed identification of the participant by a at least one vessel was classified as affected. The patholo-number known only to the investigators. Patients had gist evaluating the biopsies was unaware of the patients’to state whether they were nonsmokers, ex-smokers or smoking status.current smokers, the number of cigarettes they smokedor had smoked per day and the total number of years Statistical analysisfor calculation of pack-years until the date of biopsy. Creatinine clearance and the relative frequency of af-Patients were also questioned whether they had suffered fected glomeruli between patients with various smokinga myocardial infarction or stroke. The questionnaire was habits were compared by analysis of variance (AN-returned by 107 patients (79.3%). This return rate is OVA). The presence of arteriolar hyalinosis and of myo-identical to the one reported in the study by Orth et al intimal hyperplasia of interlobular arteries in patients of(82.1%) [10]. These 107 patients comprise the total study various smoking habits was compared using Pearson’spopulation. �2 test. Multiple regression analysis was used to identify

variables influencing the percentage of glomeruli withAdditional variablessclerosis. Logistic regression analysis was applied to ana-

The following further variables were obtained from lyze of variables influencing arteriolar hyalinosis and myo-all patients: age at time of biopsy, sex, body mass index, intimal hyperplasia. Statistical analysis was performedsystolic and diastolic blood pressure measured at the last with the Statistical Package for the Social Sciences forvisit before biopsy, creatinine clearance calculated with Windows 10.0.7 (SPSS, Inc., Chicago, IL, USA).the Cockcroft and Gault formula, 24-hour urinary pro-tein excretion determined either in a 24-hour urine sam-

RESULTSple or calculated as protein/creatinine ratio, serum cho-Patient characteristicslesterol and triglyceride levels.

The patient group consisted of 67 (62.6%) male andEvaluation of glomerular sclerosis and vascular 40 (37.4%) female subjects. Their mean age was 48 yearspathology in renal biopsies (range 30 to 74). The variables determined in these pa-

Histological evaluation of biopsies was based on the tients are shown in Table 1. Histological evaluation ofmean (range) of 13.2 (3 to 50) glomeruli, 5.4 (2 to 16) renal biopsies revealed glomerular disease in 92 patients

(86%) nephrosclerosis in eight and interstitial nephritisarterioles and 1.8 (1 to 7) interlobular arteries per biopsy.

Lhotta et al: Smoking and renal vascular pathology650

Table 3. Smoking habit of patients

Ex-smokers SmokersSmokers

N Nonsmokers % % pack-years % pack-years (Tyrolean population �16)a

All patients 107 47.7% 16.8% 27.8�24.5 35.5% 28.7�17.9 26.6%Men 67 43.3% 20.9% 32.3 �25.5 35.8% 36.1�16.5 32.6%Women 40 55.0% 10.0% 12.6�10.9 35.0% 16.6�12.9 21.4%

a Data obtained from the Austrian Microcensus 1991 [15]

Table 4. Smoking habit of patients, renal function, blood pressure, renal vascular pathology and non-renal vascular disease

Nonsmokers Ex-smokers Smokers Ever-smokers(N � 51) (N � 18) (N � 38) (N � 56)

Cr clearance mL/min 65.4�37.6 61.8�38.4 68.6�36.1 66.4�36.6Systolic RR mm Hg 148�23 156�33 156�28 156�30a

Diastolic RR mm Hg 90�12 92�18 92�16 92�16With glomerular sclerosis 32 (62.7%) 12 (66.6%) 27 (71.0%) 29 (69.6%)Affected glomeruli % 22.3�26 21.4�29.4 26.3�25.2 24.7�26.5With arteriolar hyalinosis 12 (23.5%) 5 (27.8%) 15 (39%) 20 (35.7%)b

With arterial myointimal hyperplasia 13 (25.5%) 9 (50%) 19 (50%) 28 (50%)c

Myocardial infarctione 1 (2.0%) — 2 (5.6%) 2 (3.7%)Strokee 2 (3.9%) 2 (11.1%) 4 (11.1%) 6 (11.1%)d

a P � 0.14, bP � 0.2, c P � 0.01, d P � 0.17 in comparison with nonsmokerse Data from two patients are missing

in five. One biopsy revealed normal tissue and one con- ences were observed between nonsmokers and smokers,tained only scarred tissue. A detailed list of histological ex-smokers or ever-smokers. A subgroup analysis ofdiagnoses is given in Table 2. male and female patients and of patients over fifty years

The demographic data of the 28 non-responders were of age also showed no influence of smoking on renalcomparable to those of the patients who had responded function.to the questionnaire. Out of the 28 non-responders 19

Smoking and blood pressure(67.8%) were male and nine (32.2%) female, their meanage was 50 years and renal histology revealed an underly- Ever-smokers had somewhat higher systolic blooding glomerular disease in 23 (82.1%) of them. pressure compared to nonsmokers, although the differ-

ence was not significant (P � 0.14; Table 4). DiastolicSmoking habitsblood pressure was comparable between groups.

Patient smoking habits are depicted in Table 3, wherethey are compared to the findings of an Austrian nation- Vascular pathology in renal biopsieswide questionnaire from 1991, which describes smoking The proportion of patients with partially or totallyhabits in the total population older than 16 years [14]. sclerotic glomeruli and the extent of glomerulosclerosisThe percentage of current smokers among total study

was similar among nonsmokers, ex-smokers, smokerspatients was markedly higher than in the general popula-

and ever-smokers (Table 4). Smokers and ever-smokerstion (35.5 vs. 26.6%). This increase was caused by theshowed a trend to be affected more often by renal arteri-high proportion of female smoking patients, which wasolar hyalinosis, but the difference did not reach signifi-much greater as compared to the general populationcance (P � 0.20). The proportion of patients with myo-(35 vs. 21.4%). The proportion of male smokers amongintimal hyperplasia of interlobular arteries was twice aspatients and in the Austrian Microcensus 1991 was al-high in smokers, ex-smokers and ever-smokers as com-most identical (35.8 vs. 32.6%). The percentage of malepared to the nonsmoking patients. The difference be-patients who had quit smoking was much higher thantween never-smokers and ever-smokers was statisticallyfemale patients. The number of pack-years was identi-significant (P � 0.01) (Table 4).cal between ex-smokers and current smokers. Women

smoked less than half as many pack-years than did men.Non-renal vascular disease

Smoking and renal function A tendency toward higher frequency of myocardialinfarction and especially stroke in ever-smokers was ob-Creatinine clearance for the different groups ac-

cording to smoking habit is shown in Table 4. No differ- served (P � 0.17 for stroke; Table 4). The absolute num-

Lhotta et al: Smoking and renal vascular pathology 651

Table 6. Logistic regression analysis of variables associatedTable 5. Multiple regression analysis of variables influencing thepercentage of glomeruli with sclerosis with arteriolar hyalinosis

Group and variable Coefficient SEM Pr of totalGroup and variable Coefficient SEM P model

All patients (N � 107)Systolic RR 0.024 0.009 0.005All patients (N � 107) 0.43

Systolic RR 0.422 0.087 �0.001 Smoking 0.44Male patients (N � 67)Smoking 0.76

Male patients (N � 67) 0.61 Systolic RR 0.019 0.011 0.08Smoking 0.60Systolic RR 0.296 0.122 0.0018

Body mass index 2.685 0.799 0.001 Female patients (N � 40)Systolic RR 0.031 0.015 0.036Cr clearance �0.312 0.093 0.001

Age �0.679 0.278 0.0018 Smoking 0.69Age �50 years (N � 62)Smoking 0.38

Female patients (N � 40) 0.51 Systolic RR 0.17Smoking 0.20Diastolic RR 0.875 0.242 0.001

Smoking 0.82 Age �50 years (N � 45)Systolic RR 0.069 0.024 0.004Age �50 years (N � 62) 0.55

Cr clearance �0.316 0.089 0.001 Smoking 0.61Systolic RR 0.239 0.107 0.03 Smoking was defined as never-smoking/ever-smoking.Smoking 0.69

Age �50 years (N � 45) 0.69Systolic RR 0.504 0.129 �0.001Body mass index 2.504 0.770 0.002

Table 7. Logistic regression analysis of variables associatedSmoking 0.97with myointimal hyperplasia of small arteries

Only significant variables and smoking are shown. Smoking was defined asnever-smoking/ever-smoking. Group and variable Coefficient SEM P

All patients (N � 107)Smoking 1.263 0.447 0.0047Cr clearance �0.018 0.006 0.0051

Male patients (N � 67)ber of events was small, precluding a reasonable statisti-Smoking 1.633 0.656 0.13cal analysis.Cr clearance �0.019 0.009 0.044

Female patients (N � 40)Multiple and logistic regression analyses Smoking — — 0.55

Age �50 years (N � 62)Multiple regression analysis of variables influencing the Age 0.194 0.068 0.004relative proportion of glomeruli with sclerosis showed a BMI �0.224 0.107 0.036

Cr clearance �0.021 0.011 0.044significant correlation with systolic blood pressure forSmoking 0.66the whole patient group (P � 0.001; Table 5). Smoking Age �50 years (N � 45)

was not associated with glomerulosclerosis (P � 0.76). Smoking 1.727 0.695 0.013A subgroup analysis of males and females and of patients Smoking was defined as never-smoking/ever-smoking.

under or over fifty years of age also showed no associa-tion with ever-smoking. In male patients systolic bloodpressure and body mass index showed a positive, clear-

with clearance in the whole patient group as well as inance and age a negative correlation with the relativemale patients (Table 7). In females no correlation wasproportion of sclerotic glomeruli. In females the onlyobserved. In patients under fifty years of age, age wasassociation found was with diastolic blood pressure. Pa-positively, and body mass index and clearance were nega-tients under fifty years exhibited a negative correlationtively associated with myointimal hyperplasia. In pa-with clearance and a positive one with systolic bloodtients over fifty years of age, only smoking was associatedpressure. In elderly patients systolic blood pressure andwith arterial damage.

body mass index were significantly correlated with glo-Repeating the multiple and the logistic regression

merulosclerosis. analyses using the categorization current smoker/non-Logistic regression analysis for the presence or ab- smoker instead of ever-smoker/never-smoker did not

sence of arteriolar hyalinosis also showed an association change the findings. Neither total cholesterol nor triglyc-between hyalinosis and systolic blood pressure (Table eride serum concentrations contributed significantly to6). The same association was observed in subgroup anal- the calculated models.yses in males, females and patients over and under fiftyyears of age. In younger patients a trend toward arterio-

DISCUSSIONlar changes was evident for smoking (P � 0.20).The logistic regression analysis for the presence of One of the multiple deleterious health effects of ciga-

myointimal hyperplasia showed a significant correlation rette smoking is damage to the vascular system. Smokingis an established risk factor for arteriosclerosis [15] in-of arterial damage with ever-smoking and a negative one

Lhotta et al: Smoking and renal vascular pathology652

cluding the renal arteries [16]. It also is associated with and both factors may hide any influence of smoking.Again, smoking may have an indirect damaging effectarteriolar hyalinosis and thickening of small arteries in

the kidney and various other organs [11–13], as deter- on glomeruli via blood pressure. Therefore, our studyshould not be taken as evidence against the damagingmined by autopsy studies in individuals without any

other vascular disease. Functional studies also point to effect of smoking on glomeruli and arterioles.The negative association between glomerulosclerosisa renal vascular effect of nicotine. In healthy volunteers

smoking increases blood pressure, heart rate and reno- and age in our patients is somewhat unexpected. In indi-viduals without kidney disease aging leads to progressivevascular resistance and decreases glomerular filtration

rate [17]. These effects are most likely caused by intra- glomerulosclerosis, usually causing complete sclerosisof 10 to 30% of glomeruli by the age of eighty [26].renal vasoconstriction. Smokers and ex-smokers have

reduced renal plasma flow as compared to nonsmokers Our patients, however, all suffered from kidney disease,mainly glomerulonephritis, and we also considered glo-[18]. In chronic smokers the effects of nicotine on blood

pressure and heart rate are preserved, but nicotine nei- meruli with segmental sclerosis to be affected. In addi-tion, this negative association may have been caused byther decreases renal plasma flow nor glomerular filtration

rate [19]. Both observations in smokers point to a fixed our biopsy policy, which is to perform a biopsy in youngerpatients with chronic disease and severely reduced renalnarrowing of intrarenal vessels in these individuals.

Several mechanisms may be operative in inducing re- function, but not in elderly patients.Our study was unable to show a negative effect ofnal vasoconstriction and vascular damage. Nicotine in-

creases plasma levels of vasoconstrictors such as cate- smoking on renal function. This is in contrast to theresults of Orth and colleagues in patients with IgA ne-cholamines, arginine vasopressin and endothelin-1, and

thereby causes hypertension [17, 18, 20]. It induces a phropathy [10] and of Stengel et al in patients withchronic glomerulonephritis [5], who demonstrated a det-thrombogenic state and perturbs arachidonic acid metab-

olism [21, 22]. Cigarette smoke damages endothelial rimental influence of nicotine on renal function. Ourpatient group, contrary to the other studies, includedcells, and nicotine induces smooth muscle cell prolifera-

tion [23, 24]. In consideration of these facts the assump- patients with rapidly progressive glomerulonephritis andother aggressive diseases such as proliferative lupus ne-tion that the negative effect of smoking on the course

of various kidney diseases [5–10] is caused by intrarenal phritis. In these patients who have the fastest declinein renal function, the aggressive inflammatory processvascular damage is a legitimate one. Definite proof, how-

ever, would require the demonstration of vascular changes responsible for loss of renal function probably rendersany influence of smoking undetectable. This is in linein the kidneys of patients with preexisting disease and

their correlation with smoking habits of patients in a with the observation that the loss of renal function attrib-utable to cigarette smoking seems to occur very slowlyprospective fashion. Such a study also would rely on

repeat renal biopsies. Clearly this is not feasible for ethi- [25].In female patients we were unable to demonstrate acal reasons. Our study is the first to show an association

between vascular damage in renal biopsies and smoking negative effect of smoking on small renal arteries, whichis in accordance with two other studies [5, 10]. This raiseshabits of patients with kidney disease. Indeed, we dem-

onstrate a significant correlation between ever-smoking the question whether women are protected from thenegative effects of cigarette smoking on the kidney. In alland myointimal hyperplasia of small arteries. This associ-

ation was present in the entire patient group, in patients three studies, however, the relative frequency of femalepatients was much smaller, and the proportion of femaleover fifty years of age and in men, but not in younger

patients or females. This is in accordance with other patients who smoke was considerably lower as comparedto males. Furthermore, female smokers smoked less thangroups, who also showed that smoking mainly affects

the kidney in men [5, 10] and older patients [5]. half as many pack-years as male smokers. Together witha clear dose-effect of smoking shown in previous studiesThere was a trend toward the presence of arteriolar

hyalinosis in ever-smokers that, however, did not reach [5, 10], we believe that a demonstration of a detrimentalinfluence of smoking on renal function and morphologysignificance. The main factor predicting arteriolar hyali-

nosis was systolic blood pressure. As smoking causes requires much larger cohorts of female patients thanpreviously investigated.hypertension [25], cigarette smoking may well affect ar-

terioles via high blood pressure. Only a small minority of our patients took angiotensin-converting enzyme (ACE) inhibitor treatment at theGlomerular sclerosis also did not seem to be affected

by smoking. The great majority of patients suffered from time of biopsy, and therefore we were unable to answerthe question whether such treatment abrogates vascularglomerulonephritis, and it is conceivable that in glomeru-

lonephritis glomerulosclerosis is mainly dependent on damage by tobacco abuse as suggested by Orth and col-leagues [10]. Nevertheless, ACE inhibitors have beenthe inflammatory process in the glomeruli. In addition,

blood pressure was associated with glomerulosclerosis, shown to prevent myointimal hyperplasia of small ar-

Lhotta et al: Smoking and renal vascular pathology 653

teries in various organs in animal models of chronic re- ACKNOWLEDGMENTnal failure, hypertension and after balloon angioplasty F. Kronenberg is supported by the Austrian Science Fund (P14717-

GEN).[27–29]. It is conceivable that ACE inhibitors exert theirprotective effect on smoking-induced damage to the kid-

Reprint requests to Dr. Karl Lhotta, Clinical Nephrology Division,ney by inhibiting myointimal proliferation. Department of Internal Medicine, Innsbruck University Hospital, Anich-

strasse 35, A-6020 Innsbruck. Austria.Blood pressure in our patients was much higher thanE-mail: Karl.Lhotta@uibk.ac.atthe target level for patients with renal disease and pro-

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