Departments of * Environmental Medicine, Medicine and Clinical Science, Pathophysiological and Experimental Pathology, and Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence: Drs. Toshiharu Ninomiya and Yutaka Kiyohara, Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582 Japan. Phone: +81-92-642-6104; Fax: +81-92-642-6115; E-mail: nino{at}envmed.med.kyushu-u.ac.jp for T.N., kiyohara@envmed.med.kyushu-u.ac.jp for Y.K
Correspondence: Drs. Toshiharu Ninomiya and Yutaka Kiyohara, Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582 Japan. Phone: +81-92-642-6104; Fax: +81-92-642-6115; E-mail: nino{at}envmed.med.kyushu-u.ac.jp for T.N., kiyohara{at}envmed.med.kyushu-u.ac.jp for Y.K
Received for publication January 18, 2007.
Accepted for publication April 19, 2007.
Information regarding the association between prehypertensionBP level and renal arteriosclerosis is limited. In 652 consecutivepopulation-based autopsy samples without hypertension treatmentbefore death, the relationship between the severity of renalarteriosclerosis and BP levels classified according to the criteriaof the Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressurewas examined. The age- and gender-adjusted frequencies of renalarteriosclerosis linearly increased with elevating BP levels;both hypertensive and prehypertensive subjects had significantlyhigher frequencies of renal arteriosclerosis than subjects withnormal BP (normal 11.9%; prehypertension 28.5%; stage 1 hypertension32.9%; stage 2 hypertension 58.2%; all P < 0.01 versus normal).In a logistic regression model, prehypertension was significantlyassociated with renal arteriosclerosis after adjustment forother cardiovascular risk factors (prehypertension multivariate-adjustedodds ratio [mOR] 5.99 [95% confidence interval (CI) 2.20 to15.97]; stage 1 hypertension mOR 6.99 [95% CI 2.61 to 18.72];stage 2 hypertension mOR 22.21 [95% CI 8.35 to 59.08]). Thissignificant association was observed for all renal arterialsizes. The similar association was also observed for arteriolarhyalinosis. When the subjects were divided into those with andthose without target organ damage, the impact of prehypertensionon renal arteriosclerosis was similar for both groups (subjectswithout target organ damage mOR 5.04 [95% CI 1.36 to 18.62];subjects with target organ damage mOR 6.42 [95% CI 1.29 to 32.04]).These findings suggest that both hypertension and prehypertensionare associated significantly with the severity of renal arteriosclerosis,regardless of the presence or absence of target organ damage.
Hypertension has been recognized as one of the major risk factorsfor the development of ESRD.1,2 Nephrosclerosis is characterizedpathologically by focal or global glomerular sclerosis and renalarteriosclerosis and is frequently found in individuals withhypertension.3–5 Meanwhile, several prospective studieshave indicated that the impressive increase in the risk forcardiovascular disease or in the risk for progression to hypertensionstarted at a BP level of 120/80 mmHg.6–8 On the basisof these findings, the Seventh Report of the Joint NationalCommittee on Prevention, Detection, Evaluation, and Treatmentof High Blood Pressure (JNC-7) introduced a "prehypertension"category in which BP is 120 to 139/80 to 89 mmHg and for whichhealth-promoting lifestyle modifications are recommended toprevent cardiovascular disease.9
A prospective population-based study of cardiovascular diseasehas been carried out since 1961 in the town of Hisayama on KyushuIsland in southern Japan. The most characteristic feature ofthe Hisayama Study is that the cause of death has been verifiedby autopsy for approximately 80% of deceased subjects in thestudy population.10–13 Our previous autopsy reports ofHisayama residents showed that systolic BP (SBP) was closelyrelated to the progression of glomerular sclerosis, renal arteriolarhyalinosis, and renal arteriosclerosis.12,13 To our knowledge,the Honolulu Heart Program is the only other population-basedstudy that has examined this issue, although the autopsy ratewas not high (20.6%).14,15 Their findings also suggested thatdiastolic BP (DBP) was an independent predictor of glomerularsclerosis, renal arteriolar hyalinosis, and renal arteriosclerosis.14,15However, the association between categorized BP levels and renalvascular changes was not assessed in these studies or in ours.In this study, we examined the relationship between BP levelsand renal arteriosclerosis, focusing on prehypertension, inpopulation-based autopsy samples of the Hisayama Study, takinginto account other cardiovascular risk factors as well as renalartery size.
The baseline characteristics of the 652 autopsy subjects arerepresented according to the BP levels in Table 1. The subjectswith stage 1 or stage 2 hypertension were older than those withnormal BP. The proportions of women gradually increased withelevating BP levels. The mean GFR values decreased significantlyin stage 2 hypertension relative to normal BP level, whereasserum creatinine levels did not change across BP levels. Thefrequencies of proteinuria and history of cardiovascular diseasewere significantly higher in subjects with stage 2 hypertension,and that of electrocardiogram (ECG) abnormalities increasedlinearly with elevating BP levels. The mean values of totalcholesterol were significantly higher in subjects with hypertensiveor prehypertensive BP levels, whereas the frequency of glucoseintolerance and the mean value of body mass index (BMI) didnot change across BP levels. The frequency of current smokingdecreased gradually with elevating BP levels, but no such tendencywas observed for the frequency of alcohol intake.
Table 1. Mean values or frequencies of potential risk factors and laboratory variables according to BP classification for 652 autopsy subjectsa
Figure 1 presents the age- and gender-adjusted frequencies ofrenal arteriosclerosis, arteriolar hyalinosis, and glomerularsclerosis according to BP classification. The frequencies ofrenal arteriosclerosis and arteriolar hyalinosis linearly increasedwith elevating BP levels; not only hypertensive subjects butalso prehypertensive subjects had a significantly higher frequencyof renal arteriosclerosis and arteriolar hyalinosis comparedwith subjects with normal BP. Likewise, the age- and gender-adjustedmean values of the wall-lumen ratio of renal arteries decreasedlinearly (normal 5.10; prehypertension 4.16; stage 1 hypertension3.96; stage 2 hypertension 3.47; all P < 0.01 versus normal),and those of the arteriolar hyalinosis index increased graduallywith elevating BP levels (normal 1.21; prehypertension 1.29[P < 0.05 versus normal]; stage 1 hypertension 1.29 [P <0.05]; stage 2 hypertension 1.38 [P < 0.01]). The severityof glomerular sclerosis increased significantly in only stage2 hypertension. The age- and gender-adjusted odds ratios (OR)of renal arteriosclerosis and arteriolar hyalinosis were significantlyhigher in prehypertension subjects and in hypertension subjectsthan in normal ones (Table 2). This association remained substantiallyunchanged even after adjustment for age at death, gender, totalcholesterol, glucose intolerance, BMI, smoking habits, and alcoholintake. Furthermore, we divided prehypertension into two subcategories—BP120 to 129/80 to 84 mmHg and BP 130 to 139/85 to 89 mmHg—andexamined the association between BP level and renal arteriosclerosis.As a result, the risk for having renal arteriosclerosis wassignificantly increased in both BP subcategories even afteradjustment for the previously mentioned cardiovascular riskfactors (BP 120 to 129/80 to 84 mmHg OR 5.93 [95% confidenceinterval (CI) 2.08 to 16.91; P < 0.01]; BP 130 to 139/85to 89 mmHg OR 5.92 [95% CI 2.02 to 17.29; P < 0.01]).
Figure 1. Age- and gender-adjusted frequencies of renal arteriosclerosis (A), arteriolar hyalinosis (B), and glomerular sclerosis (C) according to BP classification among 652 autopsy subjects. Solid lines indicate age- and gender-adjusted mean values of wall-lumen ratio, arteriolar hyalinosis index, and glomerular sclerosis, respectively. PreHT, prehypertension; HT, hypertension. *P < 0.05, **P < 0.01 versus normal.
Table 2. Age- and gender-adjusted or multivariate-adjusted OR for renal arteriosclerosis, arteriolar hyalinosis, and glomerular sclerosis according to BP classification among 652 autopsy subjects
We examined whether the association between BP and renal arteriosclerosisdiffers by the presence or absence of target organ damage. Asshown in Figure 2A, the age- and gender-adjusted frequenciesof renal arteriosclerosis were higher in the group with targetorgan damage than in the group without it, regardless of BPlevel. In both groups, however, the frequencies of renal arteriosclerosisincreased significantly with elevating BP levels; the differencewas significant between the normal and both the prehypertensionand hypertension categories. Likewise, the mean values of thewall-lumen ratio of renal arteries were significantly lowerin BP levels of prehypertension and hypertension than in normalBP level for both the target-organ-damaged and target-organ-undamagedgroups (Figure 2B). As shown in Table 3, the impact of prehypertensionon renal arteriosclerosis was similar for both the damaged andundamaged groups after adjustment for the previously mentionedcardiovascular risk factors (without target organ damage OR5.04 [95% CI 1.36 to 18.62; P < 0.05]; with target organdamage OR 6.42 [95% CI 1.29 to 32.04; P < 0.05]).
Figure 2. Age- and gender-adjusted frequencies of renal arteriosclerosis (A) and mean values of wall-lumen ratio of the renal arteries (B) according to BP classification by the presence or absence of target organ damage among 652 autopsy subjects. TOD, target organ damage; *P < 0.05, **P < 0.01 versus normal in target organ damage (–); $P < 0.05, $$P < 0.01 versus normal in target organ damage (+).
Table 3. Multivariate-adjusted OR for renal arteriosclerosis according to BP classification by the presence or absence of target organ damage.
Finally, we examined the associations between BP levels andrenal arteriosclerosis by the size of renal arteries using logisticregression analysis (Table 4). After adjustment for the previouslymentioned cardiovascular risk factors, both prehypertensionand hypertension significantly increased the risk for havingrenal arteriosclerosis in all arterial sizes. For smaller arteries(<300 µm), the risk for arteriosclerosis significantlyand linearly increased with elevating BP levels, whereas thislinear association was diminished for larger arteries (300 µm).
In this population-based autopsy survey, we histopathologicallyexamined the relationship between categorized BP levels classifiedaccording to the JNC-7 criteria and renal arteriosclerosis.The results showed that both hypertension and prehypertensionwere associated significantly with renal arteriosclerosis, withoutregard for the presence or absence of target organ damage orfor the size of intrarenal arteries. The relationships betweenBP and renal histopathologic changes also have been reportedin the several biopsy-based studies of living subjects. Lhottaet al.16 showed in patients who underwent biopsy that SBP wasassociated significantly with the frequencies of glomerularsclerosis and arteriolar hyalinosis. According to the studyfor patients with biopsy-proven IgA nephropathy, patients withhypertension, defined as BP 140/90 mmHg, had more severe glomerularsclerosis, interstitial fibrosis/tubular atrophy, interstitialinfiltration, and atherosclerosis compared with those withouthypertension.17 In a similar biopsy study for IgA nephropathy,prehypertension (BP 120 to 139/80 to 89 mmHg) was associatedsignificantly with the severity of mesangial proliferation andarteriolar changes, including intimal thickening, intimal duplicationor hyalinosis, but not glomerular sclerosis.18 These findingsare in accordance with those of our study.
Several recent reports have shown that the risk for the developmentof cardiovascular disease or the risk for the progression tohypertension initiates an increase in BP levels of 120/80 mmHg.A meta-analysis of individual data for 1 million adults in 61prospective studies indicated that the mortality from both ischemicheart disease and stroke increased progressively and linearlyfrom BP levels as low as SBP of 115 mmHg and DBP of 75 mmHgin middle and old age.6 In addition, longitudinal data thatwere obtained from the Framingham Heart Study indicated thathigh-normal BP and normal BP, defined by JNC-6, were associatedwith the occurrence of cardiovascular disease.7 Moreover, accordingto the randomized, controlled trial conducted in the Modificationof Diet in Renal Disease (MDRD) study, low target BP (mean BP<92 mmHg, equivalent to a BP <125/75 mmHg) reduced therisk for developing kidney failure by approximately 30% comparedwith the usual target BP (mean BP <107 mmHg, equivalent toa BP <140/90 mmHg).19 Our findings also showed that prehypertensionlevels were significantly associated with renal arteriosclerosisand arteriolar hyalinosis. It may be reasonable to suppose thatprehypertension promotes systemic arteriosclerosis includingrenal vascular changes and causes cardiovascular disease andrenal dysfunction.
It is possible that prehypertension is not the cause of renalarteriosclerosis but the result of renal vascular changes ororgan damages by other cardiovascular risk factors. In thisstudy, however, prehypertension was clearly associated withrenal arteriosclerosis, regardless of the presence or absenceof target organ damage, and this association was significanteven after adjustment for other cardiovascular risk factors.This suggests that a slight increase in BP to prehypertensionlevels was associated independently with the severity of renalarteriosclerosis. Therefore, it is possible that antihypertensivetreatment with BP-lowering <120/80 mmHg prevents the progressionof renal arteriosclerosis, regardless of the presence or absenceof target organ damage.
In our study, the relationship between BP levels and renal arteriosclerosisdiffered somewhat according to the size of renal arteries; therisk for renal arteriosclerosis increased significantly andlinearly with elevating BP levels in smaller arteries (<300µm), including arterioles, whereas this phenomenon wasdiminished in larger arteries (300 µm). Instead, the impactof total cholesterol levels was reinforced with elevating renalarterial size in our subjects (data not shown). In autopsy findingsfrom the Honolulu Heart Program, BP was associated stronglywith the intimal thickness of renal arteries with an outer diameterof 80 to 300 µm, but there were no correlations betweenthe intimal thickness of these renal arteries and other cardiovascularrisk factors, such as total cholesterol, triglycerides, bloodglucose, and smoking.14 It is feasible to speculate that thedegree of the atherogenic effects of risk factors varies accordingto artery size and that hypertension affects small arteriesnotably.
Several limitations of our study should be discussed. First,our findings might be biased by the exclusion of 187 subjectswho were taking antihypertensive medications. The mean valuesof SBP, DBP, serum creatinine, and total cholesterol and thefrequencies of proteinuria, ECG abnormalities, glucose intolerance,and history of cardiovascular disease were significantly higherand the mean values of wall-lumen ratio were significantly lowerin subjects who were taking antihypertensive medications thanin the 652 subjects without antihypertensive medications inthe present study. This bias has the potential to underestimatethe impact of hypertension or other cardiovascular risk factorson renal arteriosclerosis. However, it is unlikely that thisbias affects the association between prehypertension and renalarteriosclerosis, because prehypertensive subjects did not useantihypertensive medication. Second, only a single BP measurementwas obtained at the baseline examination in the recumbent position.This imperfect measurement of BP might have resulted in a misclassificationof our study subjects into different BP categories and a consequentdilution of our estimates of BP's impact on renal arteriosclerosis.Third, this is a cross-sectional study. Therefore, it is difficultto infer causality between prehypertension and risk for progressionof renal arteriosclerosis, because it may be presumed that BPincreased as a result of renal ischemia by preexisting renalarteriosclerosis, acting mainly through the renin-angiotensinsystem. In any case, our findings suggest that subjects withprehypertension should be considered as those with more progressiverenal arteriosclerosis. Fourth, several variables used in thisstudy were less accurate. We used the MDRD equation to estimateGFR; this formula is notoriously inaccurate in patients withnormal kidney function. Proteinuria was established as 1+ ormore on the dipstick; this would have missed all subjects withmicroalbuminuria. In addition, the definition of glucose tolerancevaried depending on when the examination was done. These factsmight lead to the misclassification of a normal subgroup withoutany risk factor and affect the cutoff value of each histologicparameter. However, it seems to be unlikely that this limitationdistorted the associations between BP levels and severity ofrenal arteriosclerosis, because BP levels showed the dosage-dependentassociation with the continuous values of wall-lumen ratio.Finally, this study is based on autopsy and the proportion ofaged people is extremely high. Therefore, its findings cannotbe applied to the overall living population. However, we believethat our findings provide useful information toward a betterunderstanding of the pathogenesis of renal arteriosclerosis.
Prehypertension level classified by JNC-7 was associated significantlywith the severity of renal arteriosclerosis. Therefore, prehypertensiveindividuals should be considered a high-risk population, regardlessof the presence or absence of target organ damage. Our findingsemphasize the need to determine whether the lowering of goalBP in hypertension management can prevent the progression ofrenal and systemic arteriosclerosis.
Study Population
The population of the town of Hisayama is approximately 7500,and data from the national census show it to be representativeof Japan as a whole.10,11 The study design and characteristicsof the subject population have been described in detail elsewhere.12,13Briefly, from January 1962 to December 1994, a total of 1742Hisayama residents of all age groups died, 1394 (80.0%) of whomunderwent autopsy. The autopsy rate was not different betweenmen (78.7%) and women (81.6%). Among these consecutive autopsysubjects, 1168 participated in at least one of the six healthexaminations conducted in 1961, 1967, 1974, 1978, 1983, and1988. For every examination, the participation rate exceeded>80% of all Hisayama residents 40 yr or older. After exclusionof 98 subjects who lacked preserved renal tissues, 33 with degeneratedor small renal tissues, 80 who underwent autopsy at other hospitals,118 who had no health examination data within 7 yr before death,and 187 who had been treated with antihypertensive medications,652 subjects (362 men and 290 women) were included in this study.The mean period from the most recent health examination to deathwas 3.6 ± 1.8 yr.
Morphologic Examination of Renal Tissue
The methods of morphologic examination of renal tissue havebeen described in detail elsewhere.13 Briefly, for light microscopicstudy, paraffin-embedded renal tissues that were obtained bystandard autopsy methods were cut at a 2-µm thicknessand stained with periodic acid-Schiff reagent. The wall-lumenratio was evaluated as the severity of arteriosclerosis by themethod of Kernohan et al.20 For each specimen, all arterieswith an outer diameter >60 µm were examined using aneyepiece micrometer. The outer diameter and the lumen diameterof the least axis of the elliptic profile were directly measured.The wall-lumen ratio was calculated in each artery as lumendiameter/(outer diameter – lumen diameter)/2, and themean value for all arteries in all subjects was used as theindex of arteriosclerosis. We further classified all arteriesinto four categories according to the outer diameters of therenal arteries—60 to 149, 150 to 299, 300 to 499, and500 µm—and calculated the mean values of the wall-lumenratio by the previously mentioned categories.
The severity of arteriolar hyalinosis was assessed semiquantitativelyby the method of Barder et al.21 For each tissue specimen, 50arterioles were examined and the severity of the lesion in eacharteriole was graded from 1+ to 4+ according to the extent ofarteriolar hyalinosis. The arteriolar hyalinosis index was calculatedby the following formula: Arteriolar hyalinosis index = (n1x1 + n2x 2 + n3x 3 + n4x 4)/50. Here, n1, n2, n3, and n4 indicatethe number of arterioles showing hyalinosis scores of 1+ to4+, respectively.
The semiquantitative score was used to evaluate the severityof glomerular sclerosis by the method of Raij et al.22 For eachtissue specimen, 100 glomeruli from the superficial to deepcortex were examined uniformly, and the severity of the lesionin each glomerulus was graded from 0 to 4+ according to thepercentage of glomerular sclerosis. The glomerular sclerosisindex was calculated by the following formula: Glomerular sclerosisindex = (n0x 0 + n1x 1 + n2x 2 + n3x 3 + n4x 4)/4. Here, n0,n1, n2, n3, and n4 indicate the number of glomeruli showingsclerotic lesion scores of 0 to 4+, respectively.
Definition of Renal Arteriosclerosis, Arteriolar Hyalinosis, and Glomerular Sclerosis
To differentiate the effects of cardiovascular risk factorsfrom age-related changes, we selected 103 subjects who had noneof the following characteristics: Proteinuria, kidney failure,hypertension, glucose intolerance, or primary renal diseaseat autopsy. Using this subgroup, the cutoff limits were definedas below the 10th percentile or above the 90th percentile ofeach histologic parameter distribution; that is, renal arteriosclerosis,arteriolar hyalinosis, and glomerular sclerosis were definedas a wall-lumen ratio <3.37, an arteriolar hyalinosis index>1.44, and a glomerular sclerosis index >17.0, respectively.In the analysis by the size of renal arteries, furthermore,renal arteriosclerosis was defined as below the lower 10th percentilefor mean values of the wall-lumen ratio by size (60 to 149 µm:wall-lumen ratio <3.56; 150 to 299 µm: wall-lumen ratio<2.65; 300 to 499 µm: wall-lumen ratio <2.64; 500µm: wall-lumen ratio <2.44).
Risk Factors
BP was measured three times after a single rest period of atleast 5 min using a standard mercury sphygmomanometer with thesubject in the recumbent position. The mean of the three measurementswas used for the analysis. BP levels were categorized accordingto the criteria recommended by JNC-79 (normal: SBP <120 mmHgand DBP <80 mmHg; prehypertension: SBP 120 to 139 mmHg orDBP 80 to 89 mmHg; stage 1 hypertension: SBP 140 to 159 mmHgor DBP 90 to 99 mmHg; stage 2 hypertension: SBP 160 mmHg orDBP 100 mmHg).
Glucose intolerance was defined by an oral glucose tolerancetest in the subjects with glycosuria in 1961 and 1967; by fastingand postprandial glucose concentrations in 1974, 1978, and 1983;and by a 75-g oral glucose tolerance test in 1988, in additionto medical history of diabetes. ECG abnormalities were definedas Minnesota codes 3-1 and/or 4-1, -2, -3. Serum total cholesterollevels were measured by the Zak-Henly method with a modificationby Yoshikawa in 1961 and 1967, by the Zurkowski method in 1974,and by the enzymatic method after 1978. Serum creatinine concentrationwas measured by the Jaffe method after 1974, and GFR was calculatedby the MDRD Study Group formula.23 Freshly voided urine sampleswere tested by the sulfosalicylic acid method in 1961 and 1967and by the dipstick method after 1974. Proteinuria was definedas 1+ or more. Body height and weight were measured in lightclothing without shoes, and the BMI (kg/m2) was calculated.Information on antihypertensive medication, alcohol intake,and smoking habits was obtained through a standard questionnaireand classified as current habitual use or a lack thereof. Allavailable information about potential cardiovascular diseases,including stroke, myocardial infarction, and coronary intervention,was gathered and reviewed by a panel of physician members ofthe Hisayama Study to determine the occurrence of cardiovasculardisease under the standard criteria. A history of cardiovasculardisease was determined on the basis of this information. Targetorgan damage was defined as the presence of ECG abnormalities,proteinuria, GFR <60 ml/min per 1.73 m2, or a history ofcardiovascular disease.
Statistical Analyses
SAS software (SAS Institute, Cary, NC) was used to perform allstatistical analyses. The crude or age- and gender-adjustedmean values and frequencies of variables were compared amongBP levels using Dunnett t test or logistic regression analysisas appropriate. The age- and gender-adjusted or multivariate-adjustedOR and 95% CI were calculated by a logistic regression analysis.P < 0.05 was considered statistically significant in allanalyses.
This study was supported in part by a Grant-in-Aid for ScientificResearch A (18209024); a grant from the Special CoordinationFund for Promoting Science; and a grant from the Technologyand Innovative Development Project in Life Sciences from theMinistry of Education, Culture, Sports, Science and Technologyof Japan.
We thank the residents of Hisayama Town for participation inthe survey and the staff of the Division of Health and Welfareof Hisayama for cooperation in this study.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
120/80 mmHg.6–8 On the basis of these findings, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) introduced a "prehypertension" category in which BP is 120 to 139/80 to 89 mmHg and for which health-promoting lifestyle modifications are recommended to prevent cardiovascular disease.9 
