Nephrol Dial Transplant (2000) 15: 1357-1366
© 2000 European Renal Association-European Dialysis and Transplant Association
What is ‘nephrosclerosis’? Lessons from the US, Japan, and Mexico
Richard E. Tracy, and
Toshiharu Ishii1
Department of Pathology, Louisiana State University Medical Center, New Orleans, LA, USA and
1 Department of Pathology, Toho University School of Medicine, Ota-ku, Tokyo, Japan
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Abstract
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Background. Selected features of ‘nephrosclerosis’
can be quantitated morphometrically in renal histology at autopsy.
Specimens are available from Japan, Mexico, and the US (blacks
and whites).
Methods. Autopsies of men and women aged 15–79 years provided renal samples for paraffin sectioning. These were assembled in New Orleans for objective evaluation after standardized staining with PAS-Alcian blue and interspersion with each other. Obsolescence of glomeruli, interstitial fibrosis, fibroplastic intimal thickenings of arteries, and arteriolar hyalinization, as operationally defined, were measured by objective morphometry.
Results. Obsolescence of glomeruli and interstitial fibrosis displayed the expected correlation with arterial intimal fibroplasia, but failed to confirm any direct association with arteriolar hyalinization. Some of the variation of ‘nephrosclerosis‘, within and between populations, cannot be fully explained by microvascular defects.
Conclusions. Arterial intimal fibroplasia appeared to promote ‘nephrosclerosis’, in the sense of fibrous replacement of atrophied nephrons, but arteriolar hyalinization did not. Hyaline deposits in arterioles may offer little or no threat to the integrity of the affected nephrons. ‘Nephrosclerosis’ appears to be multifactorial; it may be, in part, a consequence of fibroplasia in microscopic arteries causing ischaemic injury to scattered nephrons, but may also be a confluence of basically separate conditions, only some of which are known.
Keywords: aging; arteriolosclerosis; arteriosclerosis; human; hypertension
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Introduction
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The descriptive pathology of benign nephrosclerosis includes
four diagnostic features that lend themselves to precise morphometry
in paraffin sections, obsolescence of glomeruli, interstitial
fibrosis, arterial intimal fibroplasia, and arteriolar hyalinization.
The gathering together under one name, nephrosclerosis, implies
that the four histologic features are all diagnostic elements
of a single disease entity [
1]. Recent evidence, however, has
raised some doubts about such close linkages. These four features
seem at times to act independently of each other across the
groupings of age, race, sex, cause of death, and geographic
region [
2–
5]. ‘Nephrosclerosis’, when precisely
defined by objective morphometry, may not be a single disease
entity in the sense of responding to a single aetiology such
as hypertension or aging. Rather, it might often be a mixture
of several separate conditions, which jointly converge upon
a state of poor health.
A novel approach to these matters is explored here making use of a collection of specimens already assembled for another purpose [4]. In that study, the fibroplastic and the hyaline forms of vasculopathy, quantified separately, were compared with blood pressure levels obtained by community surveys in Japan and the US. The study found blood pressure to parallel fibroplastic but not hyaline vasculopathy, because hyalinization was discordantly low in autopsy samples from Japan. This report now considers a related question: does ‘nephrosclerosis’, assessed in tissue sections at autopsy as fibrous replacement of atrophied nephrons, relate equally well to fibroplastic and hyaline forms of vasculopathy, or does it relate predominantly to one or the other form? Previous studies [1,6,7] did not quantify the pathological variables or separate the hyaline from the fibroplastic forms of vasculopathy; these refinements are introduced here for the first time.
The approach taken here is to define nephrosclerosis precisely in terms of threshold values for objectively measured interstitial fibrosis and glomerular obsolescence. The condition thus defined is then related statistically to the two forms of vasculopathy, also measured objectively, with extension of the relationships across geographic boundaries.
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Subjects and methods
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Selection of cases
(i) The Toho University School of Medicine supplied renal tissues
from 270 autopsies. These tissues were from men and women of
ages 15–92 years who died from assorted causes, mostly
cancers, during 1986–1987 or from 1995 to 1996. A basal
group was constructed by excluding instances of cardiovascular
disease (CVD, 15 cases) and chronic renal diseases (15 cases),
retaining 240 cases. (ii) The Orleans Parish Coroner's Office
supplied renal tissues from 424 autopsies. Tissues were from
men and women of ages 15–102 years dying of assorted causes,
mostly violent, during 1992–1997. A basal group retained
339 cases, excluding 15 cases of chronic renal disease, and
15 cases of CVD. (iii) The Forensic Medical Service of Mexico
City supplied renal tissue from 111 autopsies. These tissues
were from men of ages 15–64 years who died as a result
of violence during 1986–1987; no instance of specific
renal disorder was encountered in the tissue sections. Further
details of these collections of specimens are available elsewhere
[
3,
4,
8]. These three cities were originally selected to compare
atherosclerosis in aortas and coronary arteries, and opportunistically
also provided renal samples. The findings reported here were
unexpected, and not intentionally sought by predesignated selection
of cities.
Basal cause of death group
Subjects that died from violent or natural causes who had no known relationship to hypertension comprise the basal group. The basal group offers a sample of the population that is approximately representative of its hypertensive prevalence [9].
Processing of renal tissues
Samples of kidney tissue were prepared as in routine autopsies. Blocks of tissue cut perpendicular to the capsular surface were fixed and stored in acetate-buffered 10% formaldehyde. Samples embedded in paraffin were sectioned at 6 µm, and stained with periodic acid Schiff-Alcian blue. Generally, a total area of renal cortex of 2–4 cm2 was represented in one or two sections. Specimens from Japan and Mexico were embedded in paraffin for transport to New Orleans, where staining and morphometry were carried out.
Morphometry of vasculopathies
Arteries in tissue sections were examined systematically under the x10 objective lens by previously reported techniques [2,5]. The outer diameter of the least axis of the elliptic profile was measured under the x10 objective lens, excluding the adventitia, and measured from one outer media to the other. The thickness of intima was measured under the x40 lens. Intimal thickness was expressed as a percentage of outer diameter, %OD (Figure 1D
), averaged over all readings within the size range of 150–300 µm OD, referred to as Rc. These arteries are believed to serve chiefly a conduit function. A similar measure averaged for vessels of 80–150 µm OD is referred to as Rr. These smaller arteries are thought to provide a significant resistance function. An average of these two measures, Ra, is used in the analyses reported here. All hyalinized vessels in the section were counted (Figures 1A and 2), and the number divided by the area of renal cortex. The ratio is expressed as the square root to reduce the severe skewness in the frequency distribution of counts of hyalinized arterioles, 
(N/cm2). Areas of inflammation or discrete scar were omitted because these can introduce severe arterial abnormalities that are not generally representative of the specimen as a whole.
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Fig. 1. (A) Hyaline deposits (arrows) in an afferent arteriole serving an intact glomerulus. (B) An obsolete glomerulus served by an intact arteriole. (C) Arteriole emerging from a fibroplastic interlobular artery is widely patent; it has arteriolar features within the intimal compartment of the parent vessel (curved arrow). (D) As in (C), but with an artefactual stricture on the emerging arteriole; the arteriole takes on a hyaline deposit after emerging (straight arrow). Measurements determine R=100(T+S)/2OD, using outer diameter (OD) and the average of two intimal thicknesses, (T+S)/2. Media is withered or absent at the ends of the OD line. PAS, bar=50 µm.
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Fig. 2. Abundant hyaline deposits in arterioles and terminal arteries (arrows) are accompanied by the absence of obsolete glomeruli or interstitial fibrosis. This is case ‘a’ in Figure 5. PAS, x120.
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The definition of ‘nephrosclerosis’
Obsolete glomeruli (Figure 1B
) were counted under the
x10 objective
lens, and the area of examined tissue measured on a projector
image [
2]. The ratio of counts (C) to area (A) was transformed
into percent of glomeruli: G=100(C/A)/160, after determining
in a sample of specimens that each cm
2 of renal cortex exhibits
an average of 160 glomerular profiles. Although other reports
[
7,
10–
13] construct a denominator for obsolete glomeruli
by counting total glomerular numbers, no advantage is known
for this operation in preference for the much more simple measurement
of tissue section area. Tubular atrophy might sometimes increase
glomerular proximity to raise C, but resorption of obsolete
glomeruli will diminish C, and no study has been done to assess
the net impact of these countervailing trends. The factor of
160 in the denominator used here is a unit conversion device
to make the values of G roughly comparable to those reported
in other studies. The arcsine transform sometimes recommended
[
10,
13] was tested, but abandoned after little advantage was
found in this particular application. Interstitial fibrosis
was graded on a 5-point scale of severity, where 1 is 0–10%
of the cortex affected; and grades 2, 3, 4, and 5 represent
11–30, 31–50, 51–70, and >70% of cortex
affected, respectively [
2]. These were assessed in all available
low-power fields, and the average recorded. The use of point
counting to determine interstitial tissue [
14–
16] is important
in needle biopsy materials, but has little to recommend it in
autopsy materials, which offer large quantities of tissue for
assessment. The features of chronic pyelonephritis were taken
to be lymphocytic infiltration, thyroidization, periglomerular
fibrosis, transcapsular fixation, and pelvic inflammation. Cases
diagnosed with chronic pyelonephritis were discarded; six such
cases were encountered. However, in practice, these features
were often seen as scattered small islands and were nearly always
present to some degree with interstitial fibrosis of grade 2
or greater, appearing to worsen with increasing arterial fibroplasia.
No reliable way has yet been developed to objectively quantify
these five features of pyelonephritis [
1]. Biases can be introduced
by exclusion or inclusion of these zones. If included, then
an inflammatory process, pyelonephritis, will sometimes exaggerate
our estimates of ‘nephrosclerosis’. If excluded,
then some scars of non-inflammatory origin are sometimes omitted,
thus biasing downward our estimate of ‘nephrosclerosis’.
It was elected to avoid the first source of bias by omitting
these features from consideration, excluding the affected areas
from morphometry. The resulting downward bias is uniformly applied
to all specimens and should have little effect on their relative
rankings. ‘Nephrosclerosis’ (Figure 3
) was categorized
in three ways: (i) a mild form has interstitial fibrosis affecting
11% of the specimen and obsolescence affecting
3% of the glomeruli;
(ii) a moderate form has fibrosis >30% and G>5%; and (iii)
a severe form has fibrosis >50% and G>5%. Type I ‘nephrosclerosis’
comprises the mild or greater degrees, and type II comprises
the moderate or greater degrees. These cutoff points are entirely
arbitrary, and have no intrinsic superiority over other possible
choices.
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Fig. 3. ‘Nephrosclerosis’, marked by fibrous replacement of atrophied nephrons, is accompanied by arterioles free of hyaline deposits (open arrows) and arteries with severe intimal fibroplasia. This case is ‘b’ in Figure 5. PAS, x120.
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Description of variables
Table 1 summarizes the foregoing list of the variables used in this report, together with descriptive information about them. The upper right triangle gives the raw product moment correlation coefficients, and the lower left triangle the age adjusted partial correlations. These statistics provide the information needed for multivariate analyses including correlation and regression.
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Table 1. Descriptive statistics for selected variables, including product moment correlation coefficients; 651 cases, total of three populations combined, excludes specific renal diseases
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Discriminating ‘nephrosclerosis’
Subjects of ages 45–79 years were grouped into those with and without ‘nephrosclerosis’, morphometrically defined by numbers of obsolete glomeruli and extent of interstitial fibrosis. Data on vasculopathies were then used to predict the diagnosis of nephrosclerosis, using discriminant function analysis. Using definition I (mild or greater), the following discriminant functions were determined, (equation 1 for a pool of all New Orleans cases and equation 2 for Tokyo; these omit 30 instances of specific renal diseases of which six were examples of chronic pyelonephritis):
 | (1) |
 | (2) |
W gives the weighted average of
Ra and Hy, which
optimally separates subjects; when
W>0, the subject is predicted
to have ‘nephrosclerosis’ by definition I, when
W<0, the subject is predicted to lack ‘nephrosclerosis’,
with the predictions based solely upon objective assessment
of microvasculature. Age and sex are rejected as not of added
statistical significance; coefficients for Hy are not significant
at
P<0.05, but are retained to help emphasize the absence
of any strong positive contribution of Hy to the weighted average,
W. Standardized coefficients are given, so that the units of
measure for
W,
Ra, and Hy are standard deviation units of the
respective variables.
T2 specifies the distance between mean
W in subjects with and without ‘nephrosclerosis’
(definition I), and is measured in units of the squared standard
deviation of
W. % is the percentage of cases correctly classified
as having or lacking ‘nephrosclerosis’ (objectively
defined) using the information on vasculopathies as described
by the equation. The standardized coefficients can be converted
back to raw units of measure by dividing each coefficient by
its appropriate standard deviation in Table 1
. When doing this,
the constant term c must be added. A version of these equations
determined for the pool of all cases from both cities is plotted
in a later graph as a solid diagonal line; another version,
similarly determined using definition II of nephrosclerosis
is also plotted as a broken line in the same graph (see Figure
5
). Those plotted equations are given here in raw units of measure:
 | (3) |
 | (4) |
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Results
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Interstitial fibrosis and obsolete glomeruli tended to rise
progressively with age in basal men of four populations and
basal women of three populations (Table 2
). The percentages
of cases classed as having ‘nephrosclerosis’ increased
with age in close parallel with the fibroplastic vasculopathy
(Figure 4
, left panel), but not with the hyaline form (Figure
4
, right panel).
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Table 2. Mean values for obsolete glomeruli and interstitial fibrosis in men of four populations and women of three populations, by 10-year age groups; basal cases only
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Fig. 4. Numerous obsolete glomeruli accompanied by fibrous replacement of 11% of the renal substance implies ‘nephrosclerosis’ by definition I (i.e. mild or greater degrees). The percentage of cases assigned to this category is plotted against mean values of fibroplastic and hyaline renovasculopathy for 10-year age groups in each population. Age groups increase from lower left to upper right in this diagram (15–24, 25–34, 35–44, 45–54, 55–64, and 65+ years at the angles of each of the lines).
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Table 3. Means of selected variables by sex group for three populations, age adjusted to mean age 45.4 years by regression; basal cases only
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Fibrous replacement of atrophied nephrons in four populations
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The four populations disclosed no simple pattern of rankings
in Table 2
. For instance, men from Tokyo had equal or greater
degrees of interstitial fibrosis than the men in the other three
populations in 16/17 comparisons within age groups, and an equal
or greater extent of obsolete glomeruli in 14/17 comparisons.
Women from Tokyo, however, equalled or exceeded the other two
populations for only interstitial fibrosis (12/12 comparisons)
but reversed this pattern for obsolete glomeruli (0/12 comparisons).
Men from Mexico had equal or greater interstitial fibrosis than
the New Orleans blacks or whites in 10/10 comparisons, but reversed
this pattern for obsolete glomeruli. New Orleans blacks did
not differ consistently or greatly from New Orleans whites in
either of these observed quantities.
Renovasculopathies in four populations
Hyalinization of arterioles (renohyaline) was lowest in the Tokyo samples. This was seen in men and women including the full range of ages in three populations (Table 3), and in the men of limited age range in four populations (Table 4). Arterial intimal fibroplasia (renofibroplasia) was lowest in the Mexico samples, although not significantly different in comparison with Tokyo (Table 4). Renofibroplasia was moderately lower in men and women from Tokyo than from New Orleans, significantly so for blacks but not for whites (Tables 3 and 4).
Relationship of obsolete glomeruli to fibroplastic and hyaline renovasculopathies at ages >44 years
Obsolete glomeruli tended to increase together with fibroplastic renovasculopathy, but not with arteriolar hyalin (Table 5). Glomeruli were 8.8% obsolete in the third of subjects with the highest renofibroplasia compared with 3.5% in the lowest third; this trend was similar at all degrees of renohyaline. Glomeruli were 5.7% obsolete in the highest compared with 5.1% in the lowest renohyaline group, an insignificant difference; similar lack of significance prevailed at all degrees of renofibroplasia.
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Table 5. Mean extent of obsolete glomeruli (percent of glomeruli) cross tabulated by fibroplastic and hyaline types of renovasculopathy; all cases age >44 years lacking specific renal disorders, age adjusted to mean age 61.1 years by regression
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Relationship of interstitial fibrosis to fibroplastic and hyaline renovasculopathies at ages >44 years
Interstitial fibrosis tended to increase together with severe arterial fibroplasia, but not with arteriolar hyalin (Table 6). The third of subjects with the highest fibroplastic renovasculopathy averaged fibrosis grade 1.9 compared with 1.3 for the lowest third; this trend was similar at all degrees of renohyaline. The third of subjects with the highest degree of renohyaline averaged fibrosis grade 1.4 compared with 1.6 for the lowest third, an insignificant difference; this lack of significance was similar at all degrees of renofibroplasia. (Technical note: the grades of 1 and 2 were assigned to specimens with respectively 0–10 and 11–30% of the nephron mass replaced by interstitial fibrosis. Group averages were grade 1.3 and 1.9 respectively in the lowest and highest arterial fibroplasia classes, which correspond to 
9.5 and 18.5% fibrosis, Table 6.)
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Table 6. Mean extent of interstitial fibrosis (5-grade scale) cross tabulated by fibroplastic and hyaline types of renovasculopathy; all cases age >44 years lacking specific renal disorders, age adjusted to mean age 61.1 years by regression
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Relationship of ‘nephrosclerosis’ to renovasculopathies in individuals of age >44 years
Cases with nephrosclerosis of ‘mild’ or ‘moderate’ degrees (definitions I or II) typically fall in the high range of renofibroplasia, but in the average range of renohyaline (open symbols shift rightward but not upward in Figure 5). The two oblique lines in the graph emphasize these relationships, because open symbols tend to be rightward and slightly downward from these lines. The solid line optimally separates the open symbols from the spots and represents equation 3, which uses definition I for ‘nephrosclerosis’. The broken line is determined using definition II (equation 4).
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Discussion
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The commonly used rubric ‘nephrosclerosis’ seems
to imply a discrete disease entity, often thought to reflect
hypertension as its sole aetiology. Yet, the diagnosis rests
ultimately on assessment of histology in tissue sections obtained
from biopsy or autopsy, and frequently lacks precision. The
approach taken here is to define ‘nephrosclerosis’
objectively by attending exclusively to morphometric indicators
for fibrous replacement of atrophied nephrons. The diagnosis
is considered positive when interstitial fibrosis and/or glomerular
obsolescence exceed certain arbitrarily imposed cutoff levels
of severity. When defined in this way, instances of nephrosclerosis
could be correctly predicted by assessment of microvasculature
in
70% of cases in this data set. The remaining 30% are presumably
related to other processes such as tubular necrosis as in shock,
interstitial nephritis, minor degrees of pyelonephritis, or
other conditions.
Subjects with morphometrically defined ‘nephrosclerosis’ in this study often displayed the most severe intimal fibroplasia of interlobular renal arteries, but only average degrees of arteriolar hyalinization. These results are shown in Figure 5, where open symbols mostly sit rightward of the nearly vertical lines in the graph. Tokyo is similar to New Orleans in this regard, as seen by comparing equations 1 and 2. These findings identify fibroplasia in the interlobular arteries, but not hyalinization of arterioles, as potential contributors to ‘nephrosclerosis’.
Comparisons between populations generally reveal a better relationship of ‘nephrosclerosis’ to fibroplastic rather than hyaline vasculopathy (Figure 4). However, some discrepancies occur in the detailed comparisons. At the ages represented in the Mexican sample, 15–54 years (excluding two cases of ages 55–64 years), the Tokyo group shows the highest rankings for both glomerular obsolescence and interstitial fibrosis, even though fibroplastic vasculopathy is greater in the New Orleans sample, significantly so for blacks (Table 4). This pattern persists in the full sample of all ages, but only for interstitial fibrosis (Table 3). These findings suggest that the causes of ‘nephrosclerosis’ can be, at least to some degree, independent of vasculopathies across geographic boundaries. The Tokyo series of cases was assembled from hospital patients while those in Mexico and New Orleans were from forensic sources. Perhaps instances of shock or toxicity of medications might explain the aberrantly high level of ‘nephrosclerosis’ in the Tokyo group.
Most subjects with ‘nephrosclerosis’ did not display exceptional degrees of arteriolar hyalinization, even after the age of 44 years (Figure 5). This statistical outcome is in keeping with usual appearances in histologic sections. Hyalinized arterioles, when seen attached to glomeruli, typically serve intact glomeruli without evidence of ischaemic injury (Figures 1A and 2). Obsolete glomeruli are seldom presented in tissue sections in a plane to show the attached arterioles; when present, these arterioles nearly always lack hyaline deposits (Figures 1B and 3). Co-existence of an obsolete glomerulus with a hyalinized arteriole is a rarity to be found only by diligent search. Drawings made from serial sections by Smith [17] seem to show this result; the 138 hyalinized arterioles included in the drawings are all depicted as attached to intact glomeruli, while only three obsolete glomeruli are shown and they have intact arterioles. Katafuchi and Takabayashi [18] reached the same conclusion from inspection of needle biopsies in hypertensive patients, ‘These data suggest that intimal thickening of the small arteries, and not hyaline change, leads to atrophy of the renal parenchyma. A possible explanation is that the hyaline change causes a less severe or no luminal occlusion of the arterioles.’ Allbutt [19] seems to adopt this view, attributing it to Ziegler, ‘... so far as I know, the first pathologist to recognize the arteriosclerotic kidney ... due primarily to sclerosis of the renal arteries with, usually but not necessarily, participation of the intimate renal ramifications also’.
The possibility arises that hyalinization of an arteriole does not ordinarily threaten the integrity of the nephron. Hyaline deposits frequently originate in youth, and evidently linger thereafter into old age, whether by endurance or by steady-state turnover [3,4,6,7]. Their apparent persistence throughout life argues that the hyaline deposits may do no harm, but may actually contribute something salutary to the affected nephrons. With ordinary immersion fixation, hyaline masses often tend toward a globular shape, as in Figure 1A, and seem to encroach upon the lumen. However, fixation by perfusion of pressurized formaldehyde into the renal artery (Figure 6) regularly deforms these globular masses into flattened or crescent shapes, and fully restores the arteriolar lumen. When inflated back into the more nearly natural position, the hyaline mass typically gives the impression of filling a bulge in the arteriolar wall where the absence of muscle cells has abolished the media, bringing endothelium into contact with adventitia (arrows in Figure 6). This filling of bulges seems to partially restore a straightened and smoothed lumen in an arteriole that is otherwise severely tortuous with uneven caliber. Perhaps these hyaline deposits serve in some way to rescue nephrons that would otherwise grow obsolete sooner.
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Fig. 6. Perfusion of 3% formaldehyde into the renal artery at 100 mmHg pressure yields appearances that contrast with immersion fixation in Figure 1A. Hyaline deposits are indicated by arrows. PAS, bar=100 µm.
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The usual descriptions of ‘nephrosclerosis’ include
severe degrees of both hyaline and fibroplastic vasculopathy,
in conflict with the finding here that most cases have only
minor degrees of hyalinized arterioles. These usual descriptions
refer only to the upper right quadrant of Figure 5
, omitting
the more abundant cases in the lower right quadrant, as if a
biased selection of cases has occurred. The source of such a
selection bias could easily be traced to the causes of death
that lead to autopsy. Subjects who happen to harbour severe
degrees of the two substantially independent processes, hyalinization
and fibroplasia, are doubly at risk of death from heart disease
or stroke [
3]. An autopsy series heavily weighted with CVD will
therefore contain many subjects in the upper right quadrant
of the chart, simply because they are patients at a particularly
high risk of death and autopsy. If such a biased sampling of
cases should occur, then it could generate a spurious correlation
of hyalinization with nephrosclerosis because of the ‘lurking
variable’, CVD [
20].
Heptinstall [1] provides a thorough review of these topics, and emphasizes glomerular hyperperfusion and ischaemia as possible causes of nephron loss together with hypertension and its renovasculopathies. As a possible source of ischaemia, strictures are sometimes seen at the ostia of afferent arterioles (Figure 1D). Although such strictures are usually absent, even when post-mortem collapse has affected the vessels (Figure 1C), they might sporadically cause the progressive loss of nephrons. It is easy to imagine that such constrictions could occur in vivo, especially during hypotensive episodes, so that ischaemia might selectively amputate the most vulnerable of scattered nephrons, leaving them to be visualized as obsolete glomeruli in a background of replacement fibrosis.
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Conclusions
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The entity ‘nephrosclerosis’ is poorly defined.
Efforts to delineate the condition by objective morphometry
are few and of limited scope [
11–
16]. Findings reported
here derive from objective quantification of operationally defined
features in renal histology. The results contain some surprises.
For instance, the fibrous replacement of atrophied nephrons
emerged with no direct relationship to arteriolar hyalinization
in this body of data. These findings might help draw attention
to this important and greatly neglected area of pathology.
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Notes
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Correspondence and offprint requests to: Dr Richard E. Tracy,
Department of Pathology, Louisiana State University Medical
Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
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Received for publication: 15. 2.00
Revision received 12. 4.00.
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Abstract
Introduction