1 University of Alexandria, Alexandria, Egypt and 2 Sheffield Kidney Institute, Sheffield, UK
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Abstract |
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Methods. Three groups were included; group I pure SN (n=16), group II a diverse group of non-schistosomal patients with comparable pathologic changes on renal biopsy (n=40) and a control group (n=5). Immunohistochemical staining of myofibroblasts (SMA and vimentin) and proliferating cells (PCNA) and histomorphometric analysis was done. In situ end labelling (ISEL) of DNA was used to evaluate apoptosis.
Results. No differences in the patterns of distribution of positivity of the different studied markers were observed between the different nephropathy groups. Both SMA and vimentin were detected in glomerular mesangial, tubular epithelial, interstitial inflammatory fibroblast-like cells and occasionally endothelial cells. PCNA and apoptotic cells were detected in tubular epithelial and interstitial cells with paucity of positive cells in the glomerulus. Significant positive correlations were detected in group I between glomerular sclerosis and interstitial markers including interstitial
SMA (r=0.609, P=0.001), interstitial vimentin (r=0.812, P=0.00) and interstitial apoptosis (r=0.733, P=0.001). On the other hand, glomerulosclerosis in group II showed significant positive correlations with predominantly the glomerular markers; glomerular
SMA (r=0.475, P=0.002), glomerular apoptosis (r=0.684, P=0.00) and glomerular PCNA (r=0.691, P=0.00). Interstitial fibrosis correlated significantly with interstitial markers in group I including interstitial
SMA (r=0.837, P=0.00) interstitial vimentin (r=0.929, P=0.00), interstitial apoptosis (r=0.807, P=0.00) and interstitial PCNA (r=0.617, P=0.01), while in group II it correlated with both interstitial and glomerular markers. In addition, the tubulo-interstitial ratio was significantly higher in group I in comparison with group II (P=0.024), with no difference between groups II and III.
Conclusions. Although SN may start as glomerulopathy associated with increased mesangial cellularity, the interstitial rather than the glomerular markers of myofibroblastic differentiation and those of cell turnover are playing a crucial role in late stages of schistosomal, but not in non-schistosomal nephropathies.
Keywords: apoptosis; SMA; myofibroblasts; PCNA; schistosomal nephropathy; vimentin
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Introduction |
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Progressive renal disease can be regarded as a disorder in which there is an abnormal regulation of cellular [6] and extracellular matrix (ECM) [7] turnover. This culminates in a progressive loss of resident cells and their replacement by inflammatory cells and fibroblasts with the associated increased deposition of ECM and fibrosis [7].
Renal cell turnover is finely balanced. Renal tissues rely on a low level of mitosis to maintain a normal number of cells [8]. Virtually every cell type seems programmed to undergo apoptosis by default unless it receives a constant and sufficient supply of survival signals. Apoptosis or programmed cell death is an established form of regulation of cell population in both glomerulus [6] and tubulo-interstitial areas [9]. In kidney diseases, apoptosis has been shown to have both beneficial and detrimental effects. It speeds up the resolution of harmful inflammation through the death of infiltrating inflammatory cells [10], but also contributes to the progressive loss of glomerular and tubular cells leading to atrophy and sclerosis [9,10].
Fibrosis is the ubiquitous companion of inflammation. It results from the proliferation of collagen-synthesizing cells, increased ECM production as well as diminished breakdown [11]. Proliferating collagen-synthesizing cells have been identified as myofibroblasts in different models of renal fibrosis [7,12,13]. The actual number of existent myofibroblasts depends on a delicate balance between their proliferation and death. It has been suggested that apoptosis of myofibroblasts allows the resolution of wound healing while their ongoing proliferation in the absence of apoptosis would lead to scarring and tissue fibrosis [14].
This study was undertaken with the aim of assessing the validity of markers of myofibroblastic differentiation (alpha smooth muscle actin (SMA) and vimentin) and those of cell turnover (proliferating cell nuclear antigen (PCNA) and apoptosis) as markers of progression in cases of SN.
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Subjects and methods |
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Histopathologic diagnoses of the different study groups are included in Table 2.
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Immunohistochemistry
Renal biopsies were fixed in 10% neutral buffered formalin, paraffin-embedded, sectioned at 4 µm and stained using a standard immunoperoxidase-staining technique. Briefly, sections were deparaffinized and rehydrated in descending grades of alcohol. Following blocking of endogenous peroxidase activity with 3% H2O2 in methanol and non-specific binding sites with a protein blocker, the primary antibody was added in the following concentrations; SMA 1:150 [7,12], vimentin 1:100 [7,12], PCNA 1:50 (Dako, UK) [15], with overnight incubation at 4°C. On day 2, the biotinylated secondary antibody (Vector, UK) was added at a concentration of 5% for 30 min followed by addition of the avidinbiotinperoxidase (ABC) complex (Vector, UK). Visualization of the reaction was performed using 3'-amino-9'-ethyl-carbimazole (AEC) (Vector) as the chromogen.
All steps were performed at room temperature in a humidity chamber unless otherwise specified. Antigen revealing techniques were used with the following antibodies: (i) anti-vimentin, cooking in microwave in 0.1 M citrate buffer for 10 min; (ii) anti-PCNA, target unmasking fluid (TUF) (Signet, UK).
Controls included sections incubated in the absence of the primary antibody as well as some incubated with a non-immune appropriate immunoglobulin.
In situ detection of apoptosis
Apoptosis was detected by in situ end labelling (ISEL) [9] of fragmented DNA using a commercial Apoptag kit (Intergen, NY, USA). Briefly, sections were deparaffinized and striped of proteins by incubation with proteinase K (Sigma, UK) in phosphate buffered saline (PBS) at room temperature for 15 min. Following washing in distilled water, endogenous peroxidase activity was quenched by 3% H2O2 for 5 min. After incubation with the equilibration buffer, the samples were incubated with terminal deoxyribonucleotidyl transferase (TdT) in reaction buffer (containing digoxigenin nucleotide) at 37°C for 60 min. The reaction was terminated using a stop buffer. Following rinsing with PBS, the tissue sections were covered with anti-digoxigenin peroxidase for 30 min at room temperature, washed in PBS, stained with AEC and counter stained with haematoxylin. Negative controls were included in each run in the form of omission of TdT in reaction buffer. Results were observed by light microscopy.
The apoptotic cells were identified by both positive staining with the apoptag immnunostain, as well as the characteristic morphology of apoptotic cells: condensed chromatin, fragmented nuclei, and pericellular halo [9,10].
Morphometric analysis
All the morphological evaluations were performed by two of the authors (A.F.E.-K. and N.B.) blinded to the section code. A standard point counting method was used to quantitate Masson trichrome stained sections for the estimation of both glomerular sclerosis (GS) and interstitial fibrosis under a magnification of x400 [12]. Twelve consecutive non-overlapping fields were evaluated in quantification of the interstitium. A total of (81x12) points were evaluated in each biopsy.
All available glomeruli in the biopsy were evaluated using a grid with 81 cross points. For the evaluation of SMA and vimentin staining, all glomeruli in the section were evaluated as well as 12 consecutive, non-overlapping fields of interstitium. All positively staining points falling on the grid's cross points were counted. The mean score per biopsy was evaluated as a per cent of positive points to the total counted.
In order to quantify the amount of apoptotic or proliferating cells in both glomerular and tubulo-interstitial compartments, 12 fields in the cortical areas of each kidney were examined at a magnification of x400 with a Reichert microscope. During evaluation of the interstitial areas, fields containing glomerular parts were ignored.
The apoptotic or proliferative indices were derived by taking the mean number of positively staining nuclei per (0.1 mm2) microscopic field. The tubulo-interstitial score was not broken down into separate tubular and interstitial cell positivity. The interstitial compartment included a mixture of interstitial fibroblast-like cells, endothelial cells, inflammatory cells and probably an unknown percentage of cells belonging to tangentially sectioned tubules.
A comprehensive regenerative index was derived from the ratio between PCNA postive cells and apoptotic cells (both glomerular and tubulo-interstitial).
Semi-quantitative histomorphometric analysis
We analysed histomorphometrically the following parameters according to an arbitrary score (from 03) used previously [13]: glomerular mesangial hypercellularity, GS, tubular atrophy, interstitial inflammation, and interstitial fibrosis (as described above).
Statitistical analysis
Results are given as mean and standard deviation (SD). Differences between the experimental groups were determined by the KruskallWallis test followed by MannWhitney U or Wilcoxon Rank sum tests for post hoc comparison. Correlations between the different parameters were performed using the Spearman's rank correlation test. Simple regression analysis using a computer-based program (SPSS) was performed. The coefficient of determination (R2) is expressed as a per cent. Results were considered significant when P value was <5%.
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Results |
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The histological classification is as described in the Subjects and methods section and in Table 2. No statistically significant difference in the frequency of the various types of glomerulonephritis was detected between the two study groups. Glomerulosclerosis was significantly higher in the nephropathies groups compared with the control group. However, no statistically significant difference was detected between the two nephropathy groups (Table 3
). Similarly, no statistically significant difference in the extent of interstitial fibrosis was detected between the two nephropathy groups (Table 3
). Interstitial inflammation was detected in 10 of 16 (62.74%) of group I patients and 20 of 40 (50%) of group II patients. Histologically, the unaffected pole of the nephrectomy specimens was normal.
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Immunohistochemistry of myofibroblastic markers
SMA expression
In the control group (group III) SMA expression was limited to the smooth muscle cellular coat of blood vessels with a few peritubular interstitial cells. In the nephropathy groups (I and II)
SMA expression was detected in the glomeruli, tubules and interstitium. No differences in the patterns of positive staining were detected between the two groups (Table 4
).
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Glomerular SMA expression
In the glomeruli, SMAs expression appeared to be mesangial in distribution. On the other hand,
SMA-positive cells decreased in sclerotic glomeruli. No difference was detected between the intensity of immunostaining of SN sections (group I) and those of the other patients (group II) (Table 4
).
SMA expression in diseased glomeruli (groups Ia, Ib and IIa, IIb) was statistically higher than that of normal kidney sections (group III) (Table 5
).
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Tubulo-interstitial SMA
Cortical interstitial expression of SMA was focal and associated with areas of interstitial fibrosis. Tubular expression of
SMA was patchy, especially in periglomerular locations. Enhanced perivascular expression of
SMA was also noted.
Both glomerular and tubulo-interstitial SMA expression was significantly higher in diseased kidneys (groups Ia, Ib and IIa, IIb) when compared with group III. However, we did not detect a difference between SN (group I) and the other nephropathies (group II) (Tables 4
and 5
).
A significant positive correlation was detected between tubular atrophy which was always maximal in periglomerular locations and each of glomerular SMA (group Ia r=0.609, P=0.047; group Ib r=0.63, P=0.021; group II both a and b were not significant) and interstitial
SMA (group Ia r=0.63, P=0.021; group Ib r=0.97, P=0.002; group IIa r=0.91, P=0.000; group IIb not significant).
Vimentin expression
Glomerular vimentin expression
In control kidneys vimentin expression was restricted to the mesangial cells. In diseased kidneys, Vimentin was detected in predominantly glomerular and interstitial locations. The intensity of the glomerular staining was always greater at the periphery of the glomerulus suggestive of a visceral epithelial cell distribution. Vimentin expression was also detected in parietal epithelial cells of Bowman's capsule and endothelial cells.
There was no difference in immunostaining pattern and intensity between schistosomal nephropathies (group I) and the others (group II) No differences in the absolute mean values of vimentin between the diseased and control kidneys were detected (Table 4).
A significant positive correlation was detected between mesangial cellularity and glomerular vimentin expression in the early groups (group Ia r=0.59, P=0.05; group IIa r=0.778, P=0.003). In the late groups (Ib and IIb) these correlations were non-existent.
Interstitial vimentin expression
Vimentin expression was seen in tubular epithelial cells in a patchy distribution especially in periglomerular locations where tubular atrophy was maximal. A characteristic basolateral distribution was noted. Some tubular epithelial cells showed intense positivity with whole cell cytoplasmic staining. Also, shed tubular epithelial cells in dilated damaged tubules expressed vimentin intensely.
A striped pattern of tubular positivity was noted, especially in the medulla. Vimentin positivity was detected in small atrophic tubules embedded in a dense fibrotic stroma while the healthy tubules were negative (tubular atrophy correlates significantly with interstitial fibrosis in all the studied groups (group Ia r=0.97, P=0.00; group Ib r=0.95, P=0.05; group IIa r=0.98, P=0.000; group IIb r=0.91, P=0.05). In the controls no tubular atrophy was detected.) Even in a single tubule, expression was seen in individual cells not in all the tubular lining cells.
Inflammatory cells in the interstitium also expressed vimentin intensely.
Interstitial vimentin immunostaining was higher in diseased kidneys compared with normal. But, we did not detect a statistical difference between the two nephropathies groups (Tables 4 and 5
).
Blood urea levels did not correlate with interstitial vimentin in groups I or II. On the other hand, serum creatinine levels showed significant positive correlations with both interstitial SMA and interstitial vimentin in group IIa (r=0.82, P=0.001; group IIb r=0.73, P=0.007).
Also, a significant correlation was detected between interstitial chronic inflammation and interstitial vimentin expression in groups Ia (r=0.76, P=0.007) and IIa (r=0.59, P=0.042).
Using stepwise regression analysis, only interstitial vimentin was found to be the strongest prognostic indicator for both GS and interstitial fibrosis in group I (61.5 and 82.4%, respectively), while both interstitial SMA and interstitial vimentin were found to equally predictive prognostic indicators for both GS and interstitial fibrosis for group II (34.2 and 65.3%, respectively, for
SMA and 32.9 and 64.1% for interstitial vimentin).
PCNA immunostaining
Glomerular
PCNA-positive cells were detected in the glomerular mesangium; however, they were scarce. Diseased kidneys had a higher number of glomerular PCNA-positive cells than control kidneys (Tables 6 and 7
). A significantly higher number of mesangial PCNA positivity was detected in group Ia as compared with IIa (Table 7
).
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Tubulo-interstitial
PCNA-positive cells were detected in the tubulo-interstitial compartment in what morphologically was identified as tubulo-epithelial cells, interstitial inflammatory cells and fibroblastic cells.
Both diseased groups (I and II) were statistically higher than the control group (III) (Tables 6 and 7
).
Although not significant, a higher number of interstitial PCNA-positive cells were detected in early schistosomal cases (group Ia as compared with IIa) (Table 7). In late cases, no difference was detected between both groups.
Tubular atrophy showed significant positive correlations with tubulo-interstitial PCNA in group Ia (r=0.69, P=0.017) and group IIa (r=0.748, P=0.005). This correlation did not exist in late cases (groups Ib and IIb).
No significant correlation was detected between interstitial chronic inflammation and interstitial PCNA positivity in any of the studied groups. While tubulo-interstitial PCNA was positively correlated with both glomerulosclerosis and interstitial fibrosis in group IIa (r=0.71, P=0.009 and r=0.85, P=0.00, respectively), it was only correlated with interstitial fibrosis in group Ia (r=0.64, P=0.035). In late cases (groups Ib and IIb), no such correlations existed (Tables 8 and 9
).
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ISEL/apoptosis staining
Glomerular
In control biopsies hardly any apoptotic cells could be detected. In diseased kidneys, apoptotic cells were detected in the mesangial compartment of the glomeruli. However, they were very scarce.
The number of apoptotic cells in groups Ia and Ib were similar in numbers (0.37 and 0.36) while if groups IIa and IIb are compared, a significant increase in the number of apoptotic cells is seen (from 0.23 to 0.58). No significant difference was detected between apoptotic cells between all groups studied (Tables 6 and 7
).
A significant correlation was detected between glomerular apoptosis and mesangial cellularity in group IIa only (r=0.71, P=0.01).
Glomerular apoptosis was positively correlated with both GS and interstitial fibrosis in group Ia. However, in IIa, it was only correlated with glomerulosclerosis (Tables 8 and 9
). In late cases, no correlation with glomerulosclerosis in either group was detected.
Tubulo-interstitial
In control biopises hardly any apoptotic cells could be detected. In diseased kidneys, apoptotic cells were detected in the tubulo-interstitial compartment, more in the medulla than in the cortex in what was morphologically identified as tubular epithelial, interstitial chronic inflammatory and interstitial fibroblastic cells.
All diseased groups were significantly higher than the control group (Tables 6 and 7
). However, no significant differences between the numbers of apoptotic interstitial cells were detected between corresponding groups. However, a significant rise in the number of apoptotic cells was detected between early and late schistosomal cases. No such difference was detected between the early and late non-schistosomal cases (Table 7
).
Also, significant positive correlations were detected between tubular atrophy and tubulo-interstitial apoptosis in both groups Ia (r=0.78, P=0.004) and IIa (r=0.82, P=0.001). In late cases no correlations existed. No significant positive correlation was detected between interstitial apoptosis and interstitial inflammation in any of the studied groups.
Regenerative ratios (PCNA-labelling index/apoptosis index)
Glomerular
The differences between individual groups did not achieve statistical significance (Tables 6 and 7
).
Tubulo-interstitial
Significant differences were detected between the studied groups as the tubulo-interstitial regenerative index was much higher in patients with SN (P=0.024) when both early and late cases in each of group I (Ia+Ib) and group II (IIa+IIb) were considered as a single group. However, on breaking down each of groups I and II into subgroups based on the available values of serum creatinine, no significant differences were detected between patients with a corresponding degree of serum creatinine as regards the tubulo-interstitial regenerative ratios (Tables 6 and 7
).
Correlations between renal scarring and the different studied parameters
When both early and late cases were considered together (i.e. Ia+Ib as a single group, IIa+IIb as a single group) GS correlated significantly with interstitial parameters of fibrosis in group I, but not with glomerular markers.
In group II, GS correlated with both glomerular (SMA) and interstitial parameters of fibrosis (Table 10
). Interstitial fibrosis in groups I and II was significantly correlated with other interstitial inflammation/scarring parameters. In group II, interstitial fibrosis was significantly correlated with glomerular markers only (Table 11
). However, in group I, GS correlated with glomerular PCNA (r=0.7, P=0.02) and glomerular apoptosis (r=0.65, P=0.03).
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Tubulo-interstitial trichrome correlated significantly with glomerular PCNA (r=0.54, P=0.001) as well as both tubulo-interstitial PCNA and apoptosis (r=0.79, P=0.001 and r=0.84, P=0.001, respectively).
A significant positive correlation was noted between glomerular SMA and glomerular apoptosis in groups Ia and Ib but not group II (both IIa and IIb) (r=0.75, P=0.008 and r=0.78, P=0.004).
Tubulo-interstitial SMA correlated significantly with interstitial apoptosis in groups Ia and IIa (r=0.67, P=0.022 and r=0.81, P=0.001, respectively).
Tubulo-interstitial SMA correlated significantly with interstitial PCNA in group IIa but not Ia (r=0.84, P=0.001). Glomerular
SMA correlated with its interstitial counterpart in group Ia (r=0.703, P=0.016) but not in group IIa. Glomerular vimentin did not correlate with its interstitial counterpart in any of the studied groups.
Differences between schistosomal (group I) and non-schostosomal cases (group II)
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Discussion |
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Similar patterns and distributions were reported previously in other forms of glomerular diseases including diabetic [12] and IgA [13] nephropathies suggesting that they represent a final common pathway of renal parenchymal cell injury.
SMA expression is considered as a marker of fibroblastic activation [14], both mesangial and tubulo-interstitial. Mesangial proliferation is a common feature of SN [16] and may represent a glomerular reaction to the deposition of schistosoma-related antigens and immune complexes [17]. We noted that such mesangial proliferation was associated with the neoexpression of actin until glomerular cellular atrophy and sclerosis prevailed when such expression decreased. The higher mesangial cellularity is a noticeable feature reflected also by the higher number of proliferating mesangial cells and the relatively lower numbers of interstitial apoptotic cells in early schistosomal as compared with early non-schistosomal cases.
Tubulo-interstitial expression of actin was prominent. SMA positivity was expressed in a range of interstitial cells including tubular cells, inflammatory cells and fibroblasts. The expression of this cytoskeletal protein in tubular cells has been reported previously [18] and suggests the possibility of the transdifferentiation of tubular cells into a fibroblastic phenotype [19]. This can be reproduced when proximal tubular cells are incubated in vitro with high concentrations of transforming growth factor-B1 (TGF-ß1) [20]. This growth factor is known to be one of the most potent stimulator of
SMA expression in fibroblasts in vivo [21] and in vitro [22].
Tubular vimentin expression is considered as a marker of injury [23]. This is supported by our observation of an increasing intensity of positivity in the shed tubular epithelial cells into the lumina of dilated tubules.
The striped pattern of expression of SMA and vimentin follows the medullary peritubular capillaries' distribution. Further, endothelial expression of vimentin in the peritubular capillaries, with their ischaemic injury, has been implicated recently in the pathogenesis of interstitial fibrosis [24]. Of note, our observation that some endothelial cells also express vimentin, is in keeping with similar observations made in the peritubular capillaries of diabetic kidneys [12]. Another intriguing possibility would attribute to peritubular capillaries' endothelial cells the capacity to transdifferentiate into myofibroblasts.
The observed perivascular accentuation of both SMA and vimentin expression may be explained by the proposed origin of myofibroblasts from pericytic cells [24].
Myofibroblasts have been established as the cells directly involved in collagen production and renal scarring in different examples of progressive nephropathy such as diabetic nephropathy [12], the renal ablation model [7], ureteric obstruction [9] and immune complex nephritis [25]. Myofibroblasts are a heterogenous group of cells expressing actin, vimentin and desmin singly or in combination [14]. A role for myofibroblasts in renal scarring is consistent with their documented role in other situations associated with fibrosis such as liver cirrhosis, lung fibrosis and wound healing [14].
Interstitial fibrosis has been positively correlated with both interstitial SMA and vimentin in all studied groups as well as with tubular atrophy, interstitial PCNA and interstitial apoptosis, especially in the early cases. This suggests that the control of interstitial cell survival by proliferation and apoptosis may play a role in the control of the volume of the interstitium and subsequently its fibrosis.
The ratio of proliferation to apoptotic cell death is a comprehensive index of the regenerative activity in the injured kidney [9]. This ratio (in the tubulo-interstitial compartment) was significantly different between the two nephropathy groups with the highest values in the schistosomal group suggesting active cellular proliferation in this group. Also, the higher numbers of proliferating (PCNA-positive) cells in the tubulo-interstitial compartment in the early cases, strengthens the theory of a higher turnover rate in the SN group as compared with the other group.
The fact that no significant differences were detected between the tubulo-interstitial regenerative ratios of the early cases in both schistosomal and non-schistosomal groups probably implies that the immune complexes deposited in the TBMs, the likely cause of the high rate of tubulo-interstitial activity in the SN group, are actually not deposited early on in the course of schisto nephropathy. This may be due to the fact that most of the blood supply of the nephron goes through the glomerulus first which acts as a filter for these immune complexes which serves to actually protect the TBMs from the effects of these immune deposits. Later on in the course of the disease when the glomeruli are saturated and possibly sclerosed, the TBMs are exposed to higher rates of immune complex deposition initiating the high inflammatory activity in the schistosomal group in late cases.
Some apoptotic cells had the morphologic characteristics of infiltrating inflammatory cells suggesting their clearance by apoptosis. On the other hand, few myofibroblasts appeared to be apoptotic, as they appeared to have ceased proliferation and were actively engaged in synthesis and laying down of collagen.
The importance of tubulo-interstitial factors in the progression of chronic renal disease has long been recognized and proven in different nephropathies such as diabetic [12] and IgA nephropathies [13]. In SN, tubulo-interstitial factors appear to play an even greater role as compared with its role in other non-SN, as evidenced by several findings in the present work; the higher tubulo-interstitial regenerative ratio in cases of SN as compared with non-schistosomal cases, the significant correlations between each of GS and interstitial fibrosis and the interstitial markers; but not with the glomerular markers, while in the non-schistosomal group significant correlations were seen with both glomerular and interstitial markers.
Other supportive findings include the higher percentage of cases in the SN group with an active tubulo-interstitial component as compared with a lower percentage in the non-schistosomal group and the higher proliferative activity in early schistosomal cases (compared with controls) in contrast to the non-schistosomal cases implying early proliferative activity in the tubulo-interstitial compartment in the schistosomal cases.
The significant increase in the apoptotic activity in the renal interstitium in the late compared with the early phase of SN in contrast to rather stable glomerular apoptotic activity, as well as the non-significant difference of the interstitial apoptotic activity between late and early phases of non-SN cases in contrast to the significant increase in the glomerular apoptotic activity, both suggest a relative important role of the renal interstitium in SN in comparison to non-SN cases.
Lastly, interstitial vimentin (considered as a marker of injury) was the strongest determining factor for the SN groups, while in the non-schistosomal group interstitial SMA (a marker of fibrosis) as well as interstitial vimentin were the strongest determining factors.
In conclusion, in the schistosomal group, it appeared that the balance between glomerular and tubulo-interstitial pathologies is even more biased toward the latter than in other types of GN.
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Notes |
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References |
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