Department of Pathology, Seoul National University College of Medicine and 1 Department of Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea
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Abstract |
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Methods. The prognostic significance of renal histological indices, such as glomerular activity index and volume density of cortical interstitium [Vv(int/cortex)], was evaluated from successive renal biopsies in 21 patients with DPLN.
Results. At the time of the second biopsies, performed an average of 43 months after the first biopsies, seven patients (33%) showed progressive renal insufficiency. Only three cases (14%) transformed to World Health Organization class I or III. The seven patients with clinical progression exhibited a higher frequency of hypertension, higher percent glomerulosclerosis, and larger Vv(int/cortex) at the time of second biopsy as compared with the 14 patients without renal insufficiency. At the first biopsy, patients with clinical progression showed a higher glomerular activity index (2.9±1.2 vs 1.3±0.8, P<0.05) and larger Vv(int/cortex) (0.13±0.07 µm3/µm3 vs 0.05±0.03 µm3/µm3, P<0.05) than the patients without progression. The glomerular activity index at the first biopsy correlated directly with per cent glomerulosclerosis, Vv(int/cortex), and serum creatinine level at the second biopsy. Vv(int/cortex) in the first biopsy also showed a significant relation with per cent glomerulosclerosis and serum creatinine level at the second biopsy.
Conclusions. These results suggest that higher glomerular activity and larger interstitial volume density at the initial biopsy can predict future progression of renal pathology or function in DPLN.
Keywords: diffuse proliferative lupus nephropathy; glomerular activity; interstitial volume density; renal prognosis; repeat renal biopsy
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Introduction |
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Many attempts have been made to define the histologic features associated with a poor renal prognosis of DPLN. Crescents with loop necrosis [2,68], the degree of inflammation or cell proliferation in glomeruli [5,9], and/or a large quantity of subendothelial deposits [1012] are regarded as important indicators of severity of glomerular disease. The composite histological scores, activity index and chronicity index, introduced by Austin et al. [6,7] have been shown to be of prognostic significance, partially or totally, in DPLN [4,7,11,1317]. In recent years, tubulointerstitial disease in SLE has been increasingly recognized as an important determinant of renal outcome [8,12,18,19].
A number of studies has evaluated repeat renal biopsies in SLE, mostly emphasizing the variable frequency of transformation from one WHO class at the time of the first biopsy to a different class at the second biopsy [3,4,20]. Recently, Esdaile et al. [12] attempted to correlate changes in biopsy variables between the two biopsies with changes in clinical parameters. Yet, no study has detected the histological factors at the initial biopsy that would predict the progression of renal pathology or function at the second biopsy.
In the present study, we examined the histological and clinical parameters that could predict the renal outcomes in 21 patients with DPLN who had undergone repeat renal biopsies. Our findings suggest that higher glomerular activity and larger interstitial volume density at the initial biopsy could predict future progression of renal pathology or function.
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Subjects and methods |
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Of the 22 patients with an initial tissue diagnosis of DPLN, 21 were selected for this study. One case with crescents affecting up to 96% of the glomeruli and a serum creatinine level of 5 mg/dl was excluded. The male to female ratio was 4 : 17. The age at the time of the first biopsy ranged from 10 to 40 years with a mean age of 22±8 years; seven patients were under 15 years of age. Hypertension, defined as a blood pressure >140/90 mmHg, was found in three cases. Seven patients had nephrotic range proteinuria 3.5 g/day. Renal insufficiency, defined as a serum creatinine level of >1.5 mg/dl, was observed in one case.
Pathological study
Renal biopsies with more than 10 glomeruli were processed for light, electron and immunofluorescence microscopy using standard methodologies. DPLN or WHO class IV is characterized by diffuse glomerular cell proliferation affecting >50% of glomeruli and the occurrence of mesangial and subendothelial deposits with or without subepithelial deposits shown with an electron microscope [22].
Light microscopic sections stained with haematoxylin and eosin, and periodic acidSchiff were semiquantitatively analysed using the scoring system of glomerular activity devised by Austin et al. [6,7] with slight modification.
Glomerular cell proliferation.
This feature included both the degree of mesangial cell proliferation and the number of infiltrating inflammatory cells in the glomerular mesangium. The lesion was scored as mild (0.5+) when the number of cells in the mesangial area was three or four, moderate (1+) when the number was five, or severe (1.5+) when it was six or more.
Crescents.
The crescent (cellular, fibrocellular) score was defined as follows: when crescents were present in <25% of glomeruli, the lesion was scored 1+; when present in 2550%, it was scored 2+; and when present in >50%, it was scored 3+.
Loop necrosis with fibrin deposition and leukocyte infiltration.
The lesion was scored 0.5+, regardless of the extent, because the weight of loop necrosis as a sign of destructive lesion was fully counted in the score of crescents.
Wire-loop formation.
The classical wire-loop lesion, caused by massive subendothelial deposits along the circumference of the luminal surface of glomerular capillaries, was scored 0.5+ when the wire-loop lesions were present in <50%, or 1+ when they were were present in >50% of glomeruli.
The maximum score for glomerular activity index was 6+.
The term glomerulosclerosis was used to describe both segmental sclerosis and global sclerosis as described by Lee and Lim [23].
Volume density of the cortical interstitium [Vv(int/cortex)] was used to describe renal cortical interstitial density and was measured in 10 consecutive cortical areas on the light microscopic sections with the method of point counting at an approximate magnification of x400 using a 100-point, calibrated, eyepiece grid as described by Lee and Lim [23]. We only counted the points lying on interstitial tissue (Pi), neglecting glomeruli, tubules and vessels. Then interstitial volume density was calculated from:
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Three pathologists (C.W.Y., M.-K.K. and H.S.L.) independently scored each biopsy for glomerular activity index and Vv(int/cortex). For glomerular activity index, the score in the consensus of the three observers was used, whereas the mean value of the three for Vv(int/cortex) was used in this study.
Statistics
Data are given as mean±standard deviation (SD). Comparisons of data between the two groups were performed using Wilcoxon's rank sum test or 2 test with stratification. The significance of the association between continuous variables was determined using regression or correlation analysis. Values of P<0.05 were deemed statistically significant.
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Results |
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Of the 21 patients, seven (33%) showed deterioration of renal function at the time of the second biopsy. None exhibited transformation of WHO class. The seven patients with clinical progression also showed a significantly higher frequency of hypertension, higher per cent glomerulosclerosis and larger interstitial volume density at the time of the second biopsy as compared with the 14 patients without progression (Table 1).
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Characteristics related to renal progression |
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Correlation of renal injury between the first and second biopsies |
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The glomerular activity index at the first biopsy of patients with DPLN correlated directly with the per cent glomerulosclerosis (r=0.67) (Figure 1), Vv(int/cortex) (r=0.63), and the serum creatinine level (r=0.65) at the time of the second biopsy (P<0.01). Vv(int/cortex) at the first biopsy was also significantly related to the per cent glomerulosclerosis (r=0.68) (Figure 2
) and the level of serum creatinine (r=0.78) at the time of the second biopsy (P<0.01).
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Discussion |
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A number of studies have evaluated repeat renal biopsies in SLE. Although transitions from one form of lupus nephropathy to another occur, they are not the rule [20,24]. In the present study, only three cases (14%) underwent histopathologic transformation. Of the remaining 18 cases without transformation, seven showed progression to a more severe lesion with an increase in serum creatinine level, blood pressure, interstitial volume density and per cent glomerulosclerosis at the second biopsy.
Glomerular activity index in the first biopsy of the patients with progression was significantly higher than that of patients without. Furthermore, the glomerular activity index in the first biopsy correlated directly with the per cent glomerulosclerosis, Vv(int/cortex), and serum creatinine level at the time of the second biopsy, suggesting that this index could predict the outcome of renal pathology or function in DPLN.
Active lesions of glomeruli may regress under steroid or cytotoxic therapy, whereas glomerulosclerosis or interstitial fibrosis progress unabated with time despite treatment [2,12]. The active glomerular lesions observed in the first biopsy of our patients with progression also tended to regress at second biopsy, partly supporting this notion. Yet the mean per cent glomerulosclerosis in the second biopsies of this progression group was up to 50%, indicating that the decreased glomerular activity index is caused by the scarring or sclerosing process of glomeruli rather than true healing. Indeed, active glomerular lesions in the first biopsy could be a bad prognosticator, requiring very careful therapy to reduce their severity.
We also found that Vv(int/cortex) in the first biopsy of patients with progression was significantly higher than that of patients without progression. Vv(int/cortex) represents not only interstitial fibrosis but also interstitial oedema and inflammation. Although interstitial oedema is potentially reversible, a persisting interstitial oedema can eventually become organized by fibroblasts into collagen [25]. Similarly, a persisting interstitial inflammatory process could result in irreversible intersititial fibrosis. Tubulointerstitial disease in SLE has been increasingly recognized as an important determinant of renal outcome in recent years [8,12,18,19]. We demonstrated that Vv(int/cortex) was significantly correlated with glomerular activity index and per cent glomerulosclerosis at the initial biopsy. Furthermore, Vv(int/cortex) in the first biopsy was significantly related to the per cent glomerulosclerosis and the level of serum creatinine at the time of the second biopsy. Thus, Vv(int/cortex) at the initial biopsy could represent not only the current status of renal damage but also its outcome several years later.
In the patients without progression, relatively low glomerular activity index and Vv(int/cortex) observed in the first biopsy remained stable in the follow-up biopsies, suggesting that maintenance of low levels of these two histological indices is important for keeping normal renal function in DPLN.
Immunosuppressive treatment generally reduced the risk of renal injury and altered the prognostic significance of histologic features in lupus nephropathy [26]. Yet our patients with a negative evolution had also received relatively sufficient therapy with prednisolone and immunosuppressive agents. Thus, it is unlikely that a different or insufficient therapeutical approach could be the cause of the different evolution of DPLN in this study.
In summary, the present study suggests that glomerular activity and interstitial volume density at the initial biopsy are useful histological indices for predicting the renal outcome in patients with DPLN. Since this conclusion was based on a retrospective study, further prospective studies are required to assess whether these histological indices significantly improve the accuracy of prognosis in each individual case.
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Acknowledgments |
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Notes |
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References |
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