Long-term renal injury in ANCA-associated vasculitis: an analysis of 31 patients with follow-up biopsies
Herbert A. Hauer1,,
Ingeborg M. Bajema4,
E. Christiaan Hagen5,
Laure-Hélène Noël6,
Franco Ferrario7,
Rüdiger Waldherr8,
Hans C. van Houwelingen2,
Philippe Lesavre6,
Renato A. Sinico7,
Fokko van der Woude9,
Gill Gaskin10,
Cornelis A. Verburgh3,
Emile de Heer1 and
Jan A. Bruijn1
1 Department of Pathology,
2 Department of Medical Statistics and
3 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands,
4 Department of Pathology, Erasmus University Medical Center Rotterdam, The Netherlands,
5 Department of Internal Medicine, Eemland Hospital, Amersfoort, The Netherlands,
6 Department of Nephrology and INSERM U507, Hôpital Necker, Paris, France,
7 Renal Immunopathology Center, Ospedale San Carlo Borromeo, Milan, Italy,
8 Department of Pathology, University of Heidelberg, Heidelberg, Germany,
9 Department of Nephrology, University of Heidelberg, Mannheim, Germany and
10 Renal Section, Hammersmith Hospital, London, UK
 |
Abstract
|
---|
Background. We reported previously that in renal disease in relation to antineutrophil cytoplasm auto-antibodies (ANCA)-associated vasculitis, renal outcome correlates better with the percentage of normal glomeruli than with separate active lesions. This may imply that glomeruli, once affected by necrotizing and crescentic lesions, are irreversibly damaged. We quantified and evaluated the course of renal lesions in the present study.
Methods. We retrospectively analysed 31 patients with renal disease in relation to ANCA-associated vasculitis, all treated with immunosuppressive drugs. In all patients, a renal biopsy was performed at diagnosis. A follow-up biopsy was performed in all patients on the indication of a suspected renal relapse, after a mean interval of 31 months.
Results. The mean percentage of normal glomeruli in the renal biopsy did not change over time (29% in the initial and 30% in the follow-up biopsy). The mean percentage of glomeruli with crescents, however, significantly decreased from 57 to 30% (P<0.001). The percentage of glomerulosclerosis significantly increased from 12 to 39% (P<0.001). The data were independent of diagnosis, gender, age, time interval between the biopsies, and treatment.
Conclusions. This is the first study to quantify glomerular changes between two time points in patients with renal vasculitis. Our results suggest that, on average, no new glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.
Keywords: ANCA-associated vasculitis; follow-up biopsies; microscopic polyangiitis; pauci-immune crescentic necrotizing glomerulonephritis; renal limited vasculitis; Wegener's granulomatosis
 |
Introduction
|
---|
In antineutrophil cytoplasm auto-antibodies (ANCA)-associated systemic vasculitis with kidney involvement, the main renal lesions are glomerular extracapillary proliferation (crescents) and fibrinoid necrosis [13]. The renal biopsy primarily serves as a diagnostic tool in combination with clinical findings and the results of ANCA serology [4]. To a lesser extent, histological parameters in the renal biopsy may be used to predict renal outcome after therapy [5].
In a previous study, we investigated the correlation between the findings in the initial renal biopsy and renal function, both at the time of biopsy and during follow-up [6]. In this clinical-pathological analysis, the renal biopsy findings at diagnosis from 157 patients with ANCA-associated systemic vasculitis were related to serum creatinine values after at least 1 year of follow-up. The percentage of normal glomeruli in the biopsy was found to be the histological parameter with the best predictive value for renal function [6]. This seems to suggest that only glomeruli that are unaffected by the disease are relevant for the re-establishment of renal function. Another hypothesis suggests that lesions considered to represent the acute phase of the disease, such as extracapillary proliferation, are to some extent reversible although there is a certain point of no return, for instance when crescents become fibrous [7]. This has implications for the effects that may be expected from therapy.
Insight into the validity of these hypotheses can only be gained in human research by studying follow-up biopsies. We present a retrospective clinical-pathological analysis of 31 patients with ANCA-associated vasculitis of whom follow-up renal biopsies were available; in these biopsies, the evolvement of renal lesions was quantified and evaluated.
 |
Subjects and methods
|
---|
Patients and renal biopsies
Clinical data and renal biopsies were available from 12 patients included in the EC/BCR Project for ANCA Assay Standardization [8]. In addition, patients were selected who were not studied in the mentioned project. Altogether, 31 patients were included in the present study from the Leiden University Medical Center (n=7), the Erasmus University Medical Center Rotterdam (n=3), The Netherlands, Hôpital Necker, Paris, France (n=7), Ospedale San Carlo Borromeo, Milan, Italy (n=9), University Clinics of Heidelberg, Germany (n=3), Addenbrooke's Hospital, Cambridge (n=1), and Hammersmith Hospital, London (n=1) UK.
Initial biopsies were performed before the onset of treatment. In the original pathology report on the initial renal biopsy, pauci-immune crescentic necrotizing glomerulonephritis was concluded in all but three cases. These were three patients with histologically proven Wegener's granulomatosis and active extra-renal disease manifestations. Two of them presented with erythrocyturia, but without elevated serum creatinine or histopathological renal lesions; the third patient presented with chronic renal lesions only. In all 31 patients, follow-up renal biopsies were performed on the indication of a suspected renal relapse, 372 months (mean 31 months) after the initial biopsy. In one case the follow-up biopsy was performed after 161 months.
Relevant clinical data at the moment of the initial biopsy and of the follow-up biopsy are listed in Table 1
, grouped by diagnosis. Patient's age at the initial biopsy ranged from 13 to 70 years (mean 49). Included were 14 females and 17 males. ANCA testing by IIF (indirect immunofluorescence test) was performed in 26 patients: 16 patients displayed a C-ANCA (cytoplasmic) staining pattern, nine a P-ANCA (perinuclear) staining pattern, and one had a negative IIF test. As some patients in this study were recruited before ANCA testing was generally in use, ANCA-test results were not available of five patients. Most patients received immunosuppressive treatment after the initial biopsy, in most cases consisting of corticosteroids in combination with either cyclophosphamide or azathioprine (Table 1
). One patient (no. 18, Table 1
) refused to receive immunosuppressive treatment. This patient proceeded to end-stage renal failure in approximately 6 months. Of another patient (no. 22, Table 1
), it remained uncertain whether he received immunosuppressive drugs or not.
Patient classification
Disease definitions were based on the Chapel Hill consensus conference on the nomenclature of systemic vasculitis [9]. Patients were categorized in the following three groups:
- (1) Wegener's granulomatosis (n=16). Histologically proven granulomatous inflammation of the respiratory tract together with necrotizing vasculitis affecting small to medium-sized vessels.
- (2) Microscopic polyangiitis (n=11). Histologically proven non-granulomatous necrotizing vasculitis predominantly affecting small vessels without airway symptoms compatible with Wegener's granulomatosis.
- (3) Renal limited vasculitis (n=4). Isolated histologically proven pauci-immune crescentic necrotizing glomerulonephritis.
Scoring of the biopsies
Paraffin sections were stained with silver, periodic acid-Schiff, haematoxylin and eosin, and trichrome, and were forwarded to two out of five participating nephropathologists (I.M.B., L.H.N., F.F., R.W., J.A.B). Both pathologists scored the biopsies separately, blinded to patient data and to the original pathology reports, and according to a previously standardized protocol for scoring renal biopsies of patients with ANCA-associated systemic vasculitis, which has been elaborately described in previous publications [6,10]. In short, each glomerulus had to be scored separately for the presence of fibrinoid necrosis, crescents, global glomerulosclerosis, or any other lesion. The number of glomeruli affected by these lesions was expressed as the percentage of the total number of glomeruli in the biopsy. The percentage of normal glomeruli was scored as well. The total percentage of glomeruli affected by the disease was calculated as the percentage of glomeruli with extracapillary proliferation plus the percentage of glomerulosclerosis. We neglected the possible influence of physiological processes of ageing on the induction of glomerulosclerosis. Interstitial infiltrates (-/+/++/+++), interstitial fibrosis (-/+/++), and tubular atrophy (-/+/++) were scored semi-quantitatively. Tubular necrosis was scored as absent or present. The arteries and arterioles were evaluated for the presence of vasculitis. The scores were entered into a central database (MSAccess) and major discrepancies between the observers were solved by conference during central reviews, achieving consensus for each biopsy.
Statistical analysis
Differences between glomerular parameters in the initial and follow-up biopsies, and renal function in terms of natural logarithm of serum creatinine at the time of these two biopsies were analysed with a paired t-test. For the interstitial parameters, this analysis was performed with the Sign test. The correlation of the histopathological differences with the differences in renal function was calculated with Spearman's rho correlation test. The influence of diagnosis, gender, and treatment (corticosteroids only vs corticosteroids and additional drugs such as cyclophosphamide and azathioprine) on our results was tested with the t-test (quantitative parameters) and with the MannWhitney U test (ordinal parameters). The influence of age and time interval between the biopsies was tested by Spearman's rho correlation test. The reported P-values are two-sided. The level of significance used was 0.05. Reported results are based on analyses in which no minimal number of glomeruli per sample was defined for inclusion of biopsies. The influence of a small number of glomeruli on the outcome of our results was tested, but it was found that both a minimum of five and ten glomeruli per biopsy as inclusion criteria did not influence these results.
 |
Results
|
---|
Results on the changes in renal histology and serum creatinine were not influenced by differences in diagnosis, time interval between the initial and follow-up biopsy, gender, patient's age, and treatment, which is shown in Table 2
. The distribution of the number of glomeruli per biopsy is illustrated in Figure 1
.
View this table:
[in this window]
[in a new window]
|
Table 2. Influence of diagnosis, gender, age, time interval between the biopsies, and treatment on differences in renal histology, and serum creatinine
|
|

View larger version (10K):
[in this window]
[in a new window]
|
Fig. 1. Distribution of sample size in terms of the number of glomeruli per biopsy in the initial biopsies (a) and in the follow-up biopsies (b). The influence of a small number of glomeruli on the outcome of our results was tested, but it was found that both a minimum of five and 10 glomeruli per biopsy as inclusion criteria did not influence these results.
|
|
Normal glomeruli
The mean percentages of normal glomeruli in the initial (29%) and follow-up (30%) biopsy were not significantly different (Table 3
and Figure 2a
). In most individual patients, the percentage of normal glomeruli in the initial and the follow-up biopsy was similar, although there were some patients with large differences as well.

View larger version (16K):
[in this window]
[in a new window]
|
Fig. 2. The percentage of normal glomeruli (a), glomeruli with fibrinoid necrosis (b), extracapillary proliferation (c), global sclerosis (d), and the calculated diseased glomeruli (e) in initial and follow-up biopsies paired for each individual. Each line counts for one patient. However, lines may overlap, in most cases between zero in the initial biopsy and zero in the follow-up biopsy. The mean percentages of glomerular lesions per biopsy with standard errors are added for both initial and follow-up biopsies.
|
|
Fibrinoid necrosis
In the initial biopsy, fibrinoid necrosis was present in 22% of all glomeruli (Table 3
and Figure 2b
) and only if extracapillary proliferation was present in the same glomerulus as well. In the follow-up biopsy, the percentage of glomeruli with fibrinoid necrosis had decreased to a mean of 8%. This difference was considered statistically significant (P=0.014).
Extracapillary proliferation
Extracapillary proliferation was present in 57% of glomeruli in the initial biopsy (Table 3
). This percentage decreased to 30% in the follow-up biopsy (P<0.001). Figure 2c
shows that the presence of extracapillary proliferation decreased between the initial and follow-up biopsy in most cases. In only a few cases, the presence of the lesion was markedly increased. Despite this significant decrease in the percentage of glomeruli affected by extracapillary proliferation, the percentage of follow-up biopsies in which crescentic glomerulonephritis (i.e. the occurrence of at least one crescent) was present did not change significantly (94% in the initial biopsy vs 87% in the follow-up biopsy).
Glomerulosclerosis
Glomerulosclerosis was present in 12% of the glomeruli in the initial biopsy (Table 3
). In the follow-up biopsy, this percentage had significantly increased to 39% (P<0.001), which is depicted in Figure 2d
. In four cases, less glomerulosclerosis was found in the follow-up biopsy than in the initial biopsy. A percentage of 100% glomerulosclerosis was not found in either the initial or in the follow-up biopsy (maximal 88%).
Diseased glomeruli
The calculated percentage of glomeruli affected by the disease appeared not to be the same as 100% minus the percentage normal glomeruli, because a few glomerular lesions not typically present in vasculitissuch as ischaemic changeswere found. In both the initial and the follow-up biopsy, the percentage of diseased glomeruli was 69% (Table 3
and Figure 2e
).
Interstitial infiltrates
Figure 3a
illustrates the results on the severity of interstitial infiltrates in the initial and follow-up biopsies, paired for each individual patient. Predominantly mild interstitial infiltrates were found in both initial and follow-up biopsies. Results on the interstitial lesions are summarized in Table 4
. Positive and negative changes in the presence of interstitial infiltrates occurred to approximately the same extent and no significant change between the initial and the follow-up biopsy was found.

View larger version (15K):
[in this window]
[in a new window]
|
Fig. 3. The severity of interstitial infiltrates (a), interstitial fibrosis (b), tubular atrophy (c), and tubular necrosis (d) in initial (diamond) and follow-up (square) biopsies paired for each individual patient. The lesions were scored on a semi-quantitative scale. Major differences of opinion were averaged.
|
|
Interstitial fibrosis
Figure 3b
illustrates that mild interstitial fibrosis was present in most initial biopsies, although absence of this lesion was frequently observed as well. In the follow-up biopsies, interstitial fibrosis was present in more cases, and it was more severe. This difference was considered significant (P=0.017) as is shown in Table 4
.
Tubular atrophy
Figure 3c
shows that tubular atrophy in all levels of severity was found in the initial biopsies. In the follow-up biopsies, the severity level was higher in most patients (Table 4
, P=0.041).
Tubular necrosis
Tubular necrosis was present in half of the initial biopsies (Figure 3d
). In the follow-up biopsies, this lesion was absent in most cases where it was present in the initial biopsy. In a few cases, tubular necrosis was found in the follow-up biopsy, whereas it was absent in the initial biopsy. These changes appeared not to be significant (Table 4
).
Interstitial vasculitis
The arteries (if present) and arterioles did not show vasculitic changes in any of the patients, neither in the initial, nor in the follow-up biopsy (data not shown).
Serum creatinine
Mean serum creatinine levels (Table 1
and Figure 4
) were elevated at the time of both the initial and the follow-up biopsy (400 and 308 mmol/l, respectively), but without a significant difference between these two time points. In the time interval between the initial and follow-up biopsy, serum creatinine levels either lowered or stabilized (data not shown).

View larger version (17K):
[in this window]
[in a new window]
|
Fig. 4. Serum creatinine levels at the time points of initial and follow-up biopsies. The mean levels of serum creatinine with standard errors are added for both time points.
|
|
Clinical-pathological correlation
The correlations between the change in renal function (in terms of the natural logarithm of serum creatinine levels) and the changes in histopathological features are shown in Table 5
. Changes in renal function significantly correlated both with changes in the percentage of normal glomeruli and with changes in the percentage of diseased glomeruli (Figure 5
).
View this table:
[in this window]
[in a new window]
|
Table 5. Correlation of differences in renal histology and difference in renal function (in terms of the natural logarithm of serum creatinine)
|
|

View larger version (7K):
[in this window]
[in a new window]
|
Fig. 5. Correlations of the change in the percentage of normal glomeruli (a) and the change in the percentage of diseased glomeruli (b) with the change in renal function (in terms of natural logarithm of serum creatinine) between the initial and the follow-up biopsy. The changes were calculated as the value at the time of the initial biopsy minus the value at the time of the follow-up biopsy.
|
|
The course of glomerular lesions
Our results on the presence of glomerular lesions in the initial and follow-up renal biopsies were used to speculate on the evolvement of these lesions during remission. This is illustrated in Figure 6
, which is a hypothesis on the course of the presence of normal glomeruli, crescents, and glomerulosclerosis in vasculitis.

View larger version (47K):
[in this window]
[in a new window]
|
Fig. 6. Hypothesis on the evolvement of normal glomeruli, extracapillary proliferation, and glomerulosclerosis during the time interval between the two biopsies. At presentation of the disease, 12% of glomeruli in the initial renal biopsy were globally sclerosed. Assuming an analogous course of events during relapse, 12% of glomeruli that were not sclerotic during remission will be sclerotic in the follow-up biopsy. Subsequently, the percentage newly sclerosed glomeruli in the follow-up biopsy (i.e. developed during relapse) can be calculated as follows: new sclerosis (follow-up)=12/100 of the not sclerotic glomeruli during remission. The not sclerotic glomeruli during remission can be substituted: new sclerosis (follow-up)=12/100 (normal (follow-up)+crescents (follow-up)+new sclerosis (follow-up)+other (follow-up)). This formula can be converted to: new sclerosis (follow-up)=12/88 (normal (follow-up)+crescents (follow-up)+other (follow-up))=12/88 (30+30+1)=8%. For the percentage sclerosis, present on average during remission, we can subsequently calculate: sclerosis (remission)=sclerosis (follow-up)-new sclerosis (follow-up)=39-8=31%. Assuming that crescents will not persist during remission without consequence on renal function and that glomerular lesions stated as other are not influenced by immunosuppressive treatment, we can calculate the percentage normal glomeruli during remission: normal (remission)=100-sclerosis (remission)-other (initial)=100-31-2=67%.
|
|
 |
Discussion
|
---|
Renal involvement is a common and usually severe feature of ANCA-associated vasculitis, which is characterized histopathologically by a pauci-immune crescentic necrotizing glomerulonephritis. How the renal histopathology changes on a long-term course is largely unknown. Insight into this issue can only be gained by studying follow-up biopsies. Only a few studies have been published discussing renal histology in follow-up biopsies [1120], and only two of these included patients with vasculitis. Aasarød et al. described 14 patients with Wegener's granulomatosis of which follow-up renal biopsies were available [20]. In 13 patients, chronicity scores had significantly increased in the follow-up biopsies as compared with the initial biopsies, but crescents were still present in eight of the cases. In a series of six patients with crescentic glomerulonephritis (of which four were pauci-immune) and follow-up biopsies (time points not stated), Kunis et al. observed persistent extracapillary proliferation in only one follow-up biopsy whereas it had been present in all initial biopsies [19]. Furthermore, the percentage of sclerotic glomeruli in the follow-up biopsy was approximately the same as the sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsy. Their results suggest that treatment prevents new crescent formation, but that it cannot prevent glomerulosclerosis of the initially affected glomeruli. This hypothesis seems in accordance with the model of crescentic glomerulonephritis in the rabbit, where collagen deposition in the glomerulus starts at the onset of extracapillary proliferation [21]. On the other hand, in this rabbit model, 90% of the glomeruli show extracapillary proliferation at the beginning of the experiment, and despite an early onset of collagen deposition, follow-up biopsies after 45 days show approximately 50% histologically normal glomeruli and global sclerosis of the other 50%. In the human situation, spontaneous improvement of crescentic glomerulonephritis sometimes occurs [7,22], although to our knowledge, this was never reported in ANCA-associated systemic vasculitis.
We present a retrospective clinical-pathological analysis of 31 patients with ANCA-associated vasculitis in which we studied the evolvement of renal histology. Initial biopsies were performed before the onset of treatment. From this time point onwards, renal function either stabilized or improved. Follow-up renal biopsies were performed for a suspected renal relapse after an interval of 372 months. Our results on the changes in renal pathology and serum creatinine were not influenced by diagnosis, gender, time interval between the biopsies, patient's age or applied treatment (corticosteroids only vs corticosteroids and additional drugs such as cyclophosphamide and azathioprine), although we should keep in mind that follow-up biopsies were performed at the indication of a suspected relapse, which may have affected the influence of these variables on our results.
The percentage of normal glomeruli in the initial and the follow-up biopsy was similar. This means that, on average, no glomeruli are recruited into the active disease process in any particular time interval in patients who receive immunosuppressive treatment and who are clinically free of relapses between both episodes. We found that the percentage of glomeruli with extracapillary proliferation was significantly lower in the follow-up biopsies, although the lesion was still present in an average of 30% of the glomeruli and in 87% of all biopsies. This lower percentage of crescents per biopsy may be due to a relatively early follow-up biopsy, with the diagnosis already established. Fibrinoid necrosis occurred in our patient group in combination with extracapillary proliferation only, which confirms our previously reported observations on this issue [23]. This means that in 13% of biopsies, no active glomerular lesions were present. The mean percentage of glomeruli affected by global sclerosis increased from 12 to 39%. Accordingly, the sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies was larger than the percentage of sclerotic glomeruli in the follow-up biopsies, which is in contrast with the results that were reported previously by Kunis et al. [19]. None of the 13% of biopsies without active lesions showed 100% glomerulosclerosis (maximal 88%), which can be explained by the fact that renal biopsies are not performed in patients with small end-stage kidneys. The current opinion on the role of immunosuppressive therapy in the treatment of renal lesions is that this type of medication has beneficial effects on at least some of the crescentic glomeruli, but not on glomerulosclerosis. Our results show that in one out of ten patients with a suspected renal relapse, no lesions or lesions insensitive to immunosuppressive drugs are found.
Figure 6
represents a hypothesis on the evolvement of normal glomeruli, extracapillary proliferation, and glomerulosclerosis during the time interval between diagnosis and the follow-up biopsy. It suggests that during therapy, a certain percentage of the glomeruli with extracapillary proliferation recover to histologically normal glomeruli and other glomeruli are doomed to develop glomerulosclerosis. This is analogous to the aforementioned rabbit model [21]. There may be a certain point of no return, after which a crescentic glomerulus loses its potential of recovering to a histologically normal glomerulus, for instance when crescents become fibrous [7]. In addition, during and after this remission induction, therapy seems to prevent normal glomeruli from being recruited into the active disease process for a certain time. We suggest that these processes result in a quiescent phase of the disease with a stable or a relatively low serum creatinine, in which no glomeruli with extracapillary proliferation are present. At the time of relapse, recovered glomeruli or glomeruli that never have been affected by the diseaseat least histologicallymay develop extracapillary proliferation and glomerulosclerosis during that stage. Alternatively, it is possible that crescents still exist during remission without largely affecting renal function.
Although interstitial fibrosis was observed in both initial and follow-up biopsies, its presence was more pronounced in the follow-up biopsies (Table 4
). For tubular atrophy, a similar pattern was observed. It is generally accepted that tubulo-interstitial disease accompanies glomerulonephritis, especially with longer duration of the disease. Various hypotheses, reviewed by Pichler et al. [24], have been suggested for the pathogenesis of tubulo-interstitial involvement in glomerulonephritis. According to these hypotheses, it is likely that the persistence of glomerular inflammation and the occurrence of glomerulosclerosis promote interstitial fibrosis and tubular atrophy.
We also investigated whether there was a correlation between the changes in renal histology and the change in renal function (Table 5
). Our results suggest that increased serum creatinine levels can be predicted neither by acute inflammation nor by chronic damage.
The main drawback of this study consists of the problem that, in current clinical practice, patients with renal disease in relation to vasculitis will not undergo a follow-up renal biopsy without medical indication, which makes prospective studies to address the evolvement of histopathological lesions on a larger scale virtually impossible. Our study comprises patients with a suspected relapse of the disease but not patients with aggressive rapidly progressive disease or patients with grumbling disease. This means that one should be cautious about drawing clinical conclusions from the present study. Future studies are needed to address this issue in depth. Furthermore, a decreased incidence of lesions that are related to irreversible injury (glomerulosclerosis, tubular atrophy, and interstitial fibrosis) was observed in the follow-up biopsies of a few patients. As the decreased incidence of these lesions did not coincide with each other, sampling error seems the most plausible explanation for this phenomenon. Finally, the retrospective character of this study makes it impossible to account for the influence of antihypertensive drugs on the histological changes between the initial and follow-up biopsy for at least three reasons. First, the year in which the initial biopsy was performed ranged from 1972 to 1996. The development in the field of antihypertensive drugs has been enormous during this period. Secondly, the time interval between the biopsies varied between 3 and 161 months. More than one antihypertensive drug will probably have been administered to patients with a long time interval between the biopsies. Finally, some patients received antihypertensive drugs not only during the interval between the biopsies, but also before systemic vasculitis had been diagnosed.
In summary, we present a study of follow-up renal biopsies in 31 patients with ANCA-associated vasculitis with renal involvement, who experienced a suspected relapse after initial treatment. This is the first study in which renal histopathological differences between biopsies performed at the moment of diagnosis and biopsies performed for a suspected renal relapse were quantified. The histological changes were independent of gender, diagnostic classification, time interval between the biopsies, patient's age, and treatment. Our results suggest that, in our patient group, on average, no glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.
 |
Acknowledgments
|
---|
We would like to thank David Jayne for kindly providing material and information of one patient in this study. Twelve of our patients were included in the European Commission/Bureau Communautaire de Référence (EC/BCR) Project for ANCA-Assay Standardisation:
Study Coordinators: E. C. Hagen, F. J. van der Woude, M. R. Daha (Leiden University Medical Center, the Netherlands). Steering Committee: G. Gaskin and C. D. Pusey (Hammersmith Hospital, London, United Kingdom), K. Andrassy (University of Heidelberg, Heidelberg, Germany), N. Rasmussen (Rigshospitalet, Copenhagen, Denmark), A. Wiik (Statens Serum Institut, Copenhagen, Denmark), F. Ferrario and R. A. Sinico (San Carlo Borromeo Hospital, Milan, Italy), Z. Heigl (Karolinska Institute, Stockholm, Sweden), D. Jayne, C. M. Lockwood (Addenbrooke's Hospital, Cambridge, UK), C. G. M. Kallenberg, J. W. Cohen Tervaert (University Hospital Groningen, the Netherlands), Ph. Lesavre (Hôpital Necker, Paris, France), J. Lüdemann (Utecht and Lüdemann, Klausdorf, Germany), F. Mascart-Lemone (Hôpital Erasme, Brussels, Belgium), E. Mirapeix (Hospital Clinic I Provincial, Barcelona, Spain), A. Tzioufas (National University of Athens, Athens, Greece), J. Wieslander (Wieslab AB, Lund, Sweden), K. de Groot, W. L. Gross (University of Lübeck, Bad Bramstedt, Germany). Pathology Review: Renal biopsies: I. M. Bajema, J. A. Bruijn (Leiden University Medical Center, the Netherlands), L. H. Noël (Hôpital Necker, Paris, France), R. Waldherr (University of Heidelberg, Heidelberg, Germany), F. Ferrario (San Carlo Borromeo Hospital, Milan, Italy). Respiratory tract biopsies: B. Ravn Juhl, C. B. Andersen (Rigshospitalet, Copenhagen, Denmark). Statistical Analysis: J. Hermans, B. E. Hansen (Leiden University Medical Center, the Netherlands). Data Management: M. J. K. Mallat (Leiden University Medical Center, the Netherlands). Participating investigators: E. Csernok (Rheumaklinik Bad Bramstedt, University of Lübeck, Bad Bramstedt, Germany), M. de Waele (Academisch Ziekenhuis Vrije Universiteit, Brussels, Belgium), W. Szpirt, J. Petersen (Rigshospitalet, Copenhagen, Denmark), C. Geffriaud (Hôpital Necker, Paris, France), G. Gregorini (Ple Spedali Civili, Brescia, Italy), M. Quarenghi (Ospedale S. Anna, Como, Italy), A. Lopez Soto (Hospital Clinic I Provincial, Barcelona, Spain), E. Pettersson (Huddinge University Hospital, Huddinge, Sweden), J. Berglund, T. Zweig, S. Jacobson (Karolinska Institute, Stockholm, Sweden), P. Chapman (Addenbrooke's Hospital, Cambridge, UK). Other Support: technical assistance: E. Heemskerk (Leiden University Medical Center, the Netherlands), A. Radice (San Carlo Borromeo Hospital, Milan, Italy), J. M. Flodman (Karolinska Institute, Stockholm, Sweden), A. Coulthart (Hammersmith Hospital, London, UK). Providing biopsy material: M. Thompson (Hammersmith Hospital, London, UK), S. Thiru (Addenbrooke's Hospital, Cambridge, UK).
 |
Notes
|
---|
Correspondence and offprint requests to: Herbert A. Hauer, Leiden University Medical Center, Department of Pathology, Building 1, L1-Q, PO Box 9600, NL-2300 RC Leiden, the Netherlands. Email: H.A.Hauer{at}LUMC.nl 
 |
References
|
---|
-
Pinching AJ, Lockwood CM, Pussell BA et al. Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q J Med1983; 208: 435460
-
Ronco P, Verroust P, Mignon F et al. Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis: a report of 43 patients with 51 renal biopsies. Q J Med1983; 206: 212223
-
Godman GC, Churg J. Wegener's granulomatosis. Pathology and review of the literature. Arch Pathol1954; 58: 533553
-
Savage COS, Harper L, Adu D. Primary systemic vasculitis. Lancet1997; 349: 553558[ISI][Medline]
-
Luqmani RA, Bacon PA, Beaman M et al. Classical versus non-renal Wegener's granulomatosis. Q J Med1994; 87: 161167[Medline]
-
Bajema IM, Hagen EC, Hermans J et al. Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis. Kidney Int1999; 56: 17511758[ISI][Medline]
-
Atkins RC, Nikolic-Paterson DJ, Song Q, Lan HY. Modulators of crescentic glomerulonephritis. J Am Soc Nephrol1996; 7: 22712278[Abstract]
-
Hagen EC, Daha MR, Hermans J et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. Kidney Int1998; 53: 743753[ISI][Medline]
-
Jennette JC, Falk RJ, Andrassy K et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum1994; 37: 187192[ISI][Medline]
-
Bajema IM, Hagen EC, Hansen BE et al. The renal histopathology in systemic vasculitis: an international survey study of inter- and intra-observer agreement. Nephrol Dial Transplant1996; 11: 19891995[Abstract]
-
Esdaile JM, Joseph L, MacKenzie T, Kashgarian M, Hayslett JP. The pathogenesis and prognosis of lupus nephritis: information from repeat renal biopsy. Semin Arthritis Rheum1993; 23: 135148[ISI][Medline]
-
Moroni G, Pasquali S, Quaglini S et al. Clinical and prognostic value of serial renal biopsies in lupus nephritis. Am J Kidney Dis1999; 34: 530539[ISI][Medline]
-
Villa M, Fogazzi GB, Ambroso GC. Crescentic glomerulonephritis with normal renal function after 28 years of follow-up. Nephrol Dial Transplant1998; 13: 26712673[Abstract]
-
Briggs WA, Tanawattanacharoen S, Choi MJ, Scheel PJ, Nadasdy T, Racusen L. Clinicopathologic correlates of prednisone treatment of human immunodeficiency virus-associated nephropathy. Am J Kidney Dis1996; 28: 618621[ISI][Medline]
-
Meyrier A, Noël LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Collaborative Group of the Societe de Nephrologie. Kidney Int1994; 45: 14461456[ISI][Medline]
-
Fukuda Y, Ohtomo Y, Kaneko K, Yabuta K. Pathologic and laboratory dynamics following the removal of the shunt in shunt nephritis. Am J Nephrol1993; 13: 7882[ISI][Medline]
-
Myers BD, Chagnac A, Golbetz H, Newton L, Strober S, Sibley RK. Extent of glomerular injury in active and resolving lupus nephritis: a theoretical analysis. Am J Physiol1991; 260: F717F727[Abstract/Free Full Text]
-
Pillemer SR, Austin HA3, Tsokos GC, Balow JE. Lupus nephritis: association between serology and renal biopsy measures. J Rheumatol1988; 15: 284288[ISI][Medline]
-
Kunis CL, Kiss B, Williams G, D'Agati V, Appel GB. Intravenous pulse cyclophosphamide therapy of crescentic glomerulonephritis. Clin Nephrol1992; 37: 17[ISI][Medline]
-
Aasarød K, Bostad L, Hammerstrom J, Jorstad S, Iversen BM. Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis. Nephrol Dial Transplant2001; 16: 953960[Abstract/Free Full Text]
-
Downer G, Phan SH, Wiggins RC. Analysis of renal fibrosis in a rabbit model of crescentic nephritis. J Clin Invest1988; 82: 9981006[ISI][Medline]
-
Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms and therapy. Am J Kidney Dis1988; 11: 449464[ISI][Medline]
-
Hauer HA, Bajema IM, de Heer E, Hermans J, Hagen EC, Bruijn JA. Distribution of renal lesions in idiopathic systemic vasculitis: a three-dimensional analysis of 87 glomeruli. Am J Kidney Dis2000; 36: 257265[ISI][Medline]
-
Pichler R, Giachelli C, Young B et al. The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: the glomerular cytokine theory. Miner Electrolyte Metab1995; 21: 317327[ISI][Medline]
Received for publication: 26. 7.01
Accepted in revised form: 14.11.01