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2012, Volume 28, Number 2, Page(s) 104-109
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DOI: 10.5146/tjpath.2012.01108 |
Association Between the Proportion of Sclerotic Glomeruli and Serum Creatinine in Primary Focal Segmental Glomerulosclerosis |
Ashraf FAKHRJOU, Ahad HASHEMPOUR, Sepideh SHADRAVAN, Rohollah Fadaei FOULADI |
Department of Pathology, Tabriz University of Medical Sciences, Imam Reza Hospital, TABRIZ, IRAN |
Keywords: Focal-segmental glomerulosclerosis, Creatinine, Creatinine metabolic clearance rate, Histopathology |
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Objective: To evaluate the possible correlation between the extent of
sclerotic glomeruli and the level of serum creatinine and its clearance
rate in patients with primary focal segmental glomerolusclerosis.
Material and Method: In a cross-sectional study, 50 patients with
biopsy-proven primary focal segmental glomerolusclerosis were
recruited. The proportion of globally and segmentally sclerosed
glomeruli was determined during the first histopathological
examination of renal biopsy specimens. Correlations of these variables
with on admission serum level of creatinine and its clearance rate
were investigated.
Results: Twenty-four males and 26 females with a mean age of
39.82±16.45 (range: 16-85) years were enrolled in the study. In
a significant fashion, the proportions of segmental and global
glomerulosclerosis were directly correlated with the serum level of
creatinine and inversely with its clearance rate (r=-0.43 with p=0.002
and r=-0.45 with p=0.001, respectively).
Conclusion: Apart from the degree of interstitial fibrosis, the serum
level of creatinine and its clearance rate are well correlated with the
proportions of both segmentally and globally sclerosed glomeruli in
primary focal segmental glomerulosclerosis. |
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Focal segmental glomerolusclerosis (FSGS) was described
for the first time in 1957 as a condition characterized by
asymptomatic proteinuria or varying degrees of nephrotic
syndrome with or without renal insufficiency 1. Although
the diagnosis is made merely on the histopathological
findings, the clinical symptoms could be regarded as
precious 2. Probable contributing factors to primary glomerular injury and glomerolusclerosis (GS) are generally
unknown 3; however, it is thought that injury of podocytes,
proliferative changes in endothelial, epithelial and mesangial
cells, structural alterations in glomerular arterioles; and
finally, development of sclerosis underlie this condition 4. A number of viruses, toxins and intraglomerular
hemodynamic changes have been suspected as the culprits 5. On histopathologic examination a segmental perihilar or peripheral solidification of glomerular tuft usually with
involvement of the tubular pole is common. However,
histopathologic alteration in the renal tissue varies greatly,
ranging from observation of normal glomeruli to segmental
or global GS. Typical classification in this regard includes
collapsing FSGS, cellular FSGS, tip-lesion, perihilar and nototherwise
specified (NO S) 6. Although varying degrees of
proteinuria along with hyaline and wide waxy casts may be
detected in urinary analysis, red blood cell (RBC) casts are
rare 7. As in other pathologies of the kidney, the serum
creatinine and its clearance rate serve as valuable indicators
of renal function 8,9. However, they might lie in normal
ranges in the early phase of the disease 10. It has been
previously proposed that the renal function may reflect
the extent of interstitial fibrosis 11-16, but this could not
satisfyingly justify abnormalities in serum creatinine and its
clearance in FSGS cases with no or mild interstitial fibrosis.
It is not well recognized whether the serum creatinine or its
clearance rate could be employed as good surrogates for the
extent of segmentally or globally sclerosis of glomeruli in
primary FSGS. Thus, this study aimed to assess the possible
association between the extent of glomerular sclerosis and
renal function in patients with FSGS and rather spared
interstitial tissue. |
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Abstract
Introduction
Methods
Results
Disscussion
Conclusion
References
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In this cross-sectional study, 50 patients with biopsy-proven
primary FSGS were recruited from Imam Reza Teaching
Centre, Tabriz, Iran from March 2009 through July
2011. Cases with systemic diseases, primary or secondary
glomerulopathies, a history of reflux and hepatitis B infection,
and moderate to severe interstitial involvement in
histopathologic assessment were not included. This study
was approved by the Ethics Committee of Tabriz University
of Medical Sciences and an informed consent was obtained
from all participants at the time of enrollment.
A comprehensive evaluation, including a thorough historytaking
and physical examination, as well as a complete
laboratory evaluation such as urinalysis, 24-h urinary
protein excretion, creatinine clearance (CCr), serum and
urinary levels of creatinine, cholesterol, albumin, fasting
blood glucose, and other tests to exclude systemic diseases as
appropriate, were performed at the time of initial evaluation.
CCr was calculated from the creatinine concentration in the
collected urine sample (UCr), urine flow rate (V), and the
plasma concentration (PCr) by this formula4:
Ccr=(Ucr*V)/Pcr
Potential confounding causes of creatinine rise were ruled
out by a skilled nephrologist before histopathologic assessments.
Renal specimens were obtained in all patients by
percutaneous biopsy, and sections containing at least eight
glomeruli were examined by a single skilled nephropathologist.
Repeat biopsies following the diagnosis of FSGS were
not included. The nephropathologist was blinded to the clinical
and laboratory details of the patients.
The specimens were stained by Masson trichrome, Congo
red, Periodic acid-Schiff (PAS) and Hematoxylin&Eosin and
examined by light microscopy and immunofluorescence
(Olympus™, PA, USA). The immunofluorescence findings
were as follows: positive IgM and C3, as well as negative IgG,
IgG, C4, C1q and fibrin/fibrinogen. On histopathologic
assessment the interstitium showed mild to moderate
patchy mononuclear inflammatory cell infiltration and
fibrosis was mild and patchy. Tubular atrophy was about
30% up to 55% especially around affected glomeruli.
Arterioles showed subintimal hyalinization and arteries
show medial hypertrophy.
FSGS was defined based on the following criteria: (i) a
lesion involving only some of the glomeruli in the biopsy
with others remaining uninvolved, (ii) the involved
glomeruli having a segmental sclerotic lesion with or
without discrete capsular adhesions, and (iii) no clinical or
pathological evidence for underlying primary disease that
might produce secondary sclerosis.
Along with the first histopathological diagnosis of FSGS,
segmentally and globally sclerosed glomeruli were counted
separately in each field. At the same time, total glomerular
count was also determined and then the proportion
of segmentally and globally sclerosed glomeruli was
calculated. The sclerotic score was determined based on
following classification6:
I: Involvement <25% of total glomeruli
II: Involvement of 26%-75% of total glomeruli
III: Involvement >76% of total glomeruli
To assess errors of measurement, total glomeruli, as
well as the segmentally and globally sclerosed glomeruli
were recounted in 10 specimens selected randomly on
2 consecutive days by the same observer. Data from the
two sets of measurements were compared. The limits of
agreements were acceptable (i.e. within the 5% of the mean
value).
Correlations of the number and proportion of segmentally
or globally sclerosed glomeruli with serum level of
creatinine and its clearance rate were examined. Other
investigated variables in the current study were the patients’
age, gender and weight.
Statistical analysis
Statistical evaluation was made using SPSS for Windows V
18.0 (SPSS Inc., Il, USA). The independent samples T-test,
Mann-Whitney U-test, Chi-square test or Fisher’s exact
test were employed for comparison where appropriate.
Correlation between different variables was examined by
calculating the Spearman’s rho coefficient. P values less
than 0.05 were regarded as significant. |
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Abstract
Introduction
Methods
Results
Disscussion
Conclusion
References
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Demographics and general data of the studied population
are outlined in Table I. Correlations between the
proportion of sclerosed glomeruli and different variables
are summarized in Table II. The proportion of segmentally
sclerosed glomeruli was significantly correlated with
the serum level of creatinine directly (Figure 1), and the
creatinine clearance rate inversely (Figure 2). Similar
relationships were also present between the proportions of
globally sclerosed glomeruli and the mentioned variables
(Figures 3 and 4). The other correlations did not reach
statistically significant levels. In comparison between
the males and females, neither the mean proportion
of segmentally sclerosed glomeruli (45.49±22.71 and
43.53±19.68, respectively; p=0.86), nor the mean
proportion of globally sclerosed glomeruli (36.11±16.23
and 30.19±12.77, respectively; p=0.16) were significantly
different. Associations of the glomerulosclerotic scores
with the level of serum creatinine and its clearance rate are
summarized in Table III. Accordingly, the median level of
serum creatinine was significantly higher in patients with scores II or III segmental or global GS comparing with those
in patients with score II segmental or global GS. Median clearance of creatinine was significantly higher in patients
with score I global GS comparing with that in patients with
score II global GS.
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Table I: Demographics and general data of the studied
patients with focal segmental glomerulosclerosis |
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Table II: Correlations between the proportion of sclerosed glomeruli and other variables |
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Figure 1: The scatter diagram of segmentally sclerosed glomeruli
versus serum creatinine. |
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Figure 2: The scatter diagram of segmentally sclerosed glomeruli
versus creatinine clearance. |
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Figure 3: The scatter diagram of globally sclerosed glomeruli
versus serum creatinine. |
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Figure 4: The scatter diagram of globally sclerosed glomeruli
versus creatinine clearance. |
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Table III: Association between the glomerulosclerotic scores and level of serum creatinine and its clearance rate |
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Abstract
Introduction
Methods
Results
Disscussion
Conclusion
References
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The natural course of FSGS is gradual and progressive
compromise of renal function and finally, development
of ESRD within 5-10 years. Nevertheless, this course is
variable and the prognosis may be unpredictable. So,
many efforts have been ever made to employ some clinical
and histopathologic aspects of the disease to predict its
course 10. Serum creatinine and its clearance have been
proposed in this regard; however, the data are scarce and inconclusive 6. In this study correlations between the
number of sclerosed glomeruli in one hand, and serum
level of creatinine and its clearance rate in other hand were
investigated in patients with primary FSGS. Based on the
findings, there were significant direct correlations between
proportions of segmental or global GS and serum level of
creatinine. There were also inverse correlations between
proportions of segmental or global GS and clearance of
serum creatinine. In one of avant-garde studies, Lee and
Spargo recruited 60 patients with idiopathic FSGS and
showed that the severity of renal hyaline arteriosclerosis
and global GS was correlated well with the serum level of
creatinine and its clearance rate 11. Their findings are partly in line with ours, namely in association of global
GS and serum level of creatinine and its clearance rate.
On the contrary, however, Chiang et al. did not find any
significant association between the severity of vacuolization
in epithelial cells and clearance of creatinine in 10 patients
with primary FSGS 12. Although small sample size was
a major limitation, this study may indicate indirectly that
other histopathologic changes rather than vacuolated
epithelial cells may be connected to changes in serum level
of creatinine in patients with FSGS. Schwartz et al. studied
81 patients with primary FSGS and showed a significant
direct association between the serum level of creatinine and
degree of interstitial fibrosis. However, similar associations
were not significantly apparent with the extent of segmental
scar, diffuse mesangial hypercellularity and presence of
lesions in glomerular epithelial cells 13. A wide range
of histopathologic changes has been described in patients
with FSGS and these may very greatly in even clinically
similar cases. This variability may be regarded as one of the
underlying etiology of heterogeneity in different settings.
Another example is the results of study by Lee and Kim on
11 patients with primary FSGS. They reported significant
reverse association between the ratio of mesangial volume
and clearance of creatinine and direct association between
the size of basal membrane of peripheral glomeruli and
clearance of creatinine. However, they did not report any
significant association between the density of interstitial
volume and clearance of creatinine 14. In another series
by Rydel et al. on 81 patients with primary FSGS, there was
significant direct association between the serum level of
creatinine and degree of interstitial fibrosis 15. Danilewicz
et al. enrolled 15 patients with primary FSGS in their
study. There was a significant direct association between
the interstitial volume and serum level of creatinine, as
well as significant correlations between the volume of
glomerular mesangium and total glomerular area with
serum creatinine. They concluded that the glomerular
hypertrophy and interstitial fibrosis are valuable predictors
of prognosis in patients with primary FSGS 16. In a recent
study by Taheri et al., 64 patients with primary FSGS were
assessed. There were direct associations between the serum
level of creatinine and extent of adhesions in Bowman’s
capsule, interstitial fibrosis and global scar 10. It is clear
that the sclerotic changes in glomeruli of patients with
FSGS may lead to interstitial fibrosis 6. By the way, it is
generally accepted by pathologists that a shared feature in
all cases with FSGS is the sclerosis 4. However, it should
be born in mind that our study is the first one which deals
with association of glomerular sclerosis and changes of
serum creatinine and its clearance in a totally quantitative fashion. Likewise, our selecting criteria in terms of
concomitant histopathologic changes in the interstitium
have restricted interfering effects of other histopathologic
changes routinely seen in patients with FSGS other than
the glomerular sclerosis. Overall, unlike previous reports
which focused on the role of histopathologic changes in the
interstitial tissue in alteration of renal function in FSGS, we
showed exclusively that glomerular sclerosis should not be
overlooked in this regard. |
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Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
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Serum level of creatinine and its clearance rate are good
indicators of extent and severity of segmental or global
glomerular sclerosis in patients with primary FSGS. This
association seems to be distinct from others, particularly
that one between the interstitial histopathologic changes
and function of kidney in these patients. |
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Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
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Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
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