Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis
Knut Aasarød1,,
Leif Bostad2,
Jens Hammerstrøm1,
Størker Jørstad1 and
Bjarne M. Iversen3
1 Department of Medicine, University Hospital of Trondheim, The Norwegian Kidney Register,
2 Department of Pathology
3 Institute of Medicine, Haukeland University Hospital, Bergen, Norway
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Abstract
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Background. The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease.
Methods. Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5184).
Results. Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (
=0.52, P=0.0004), with necrosis (
=0.36, P=0.002) and with the percentage of normal glomeruli (
=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (±26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment.
Conclusion. Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.
Keywords: clinical course; glomerular lesions; immunohistochemistry; renal biopsy; renal histopathology; Wegener's granulomatosis
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Introduction
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Wegener's granulomatosis (WG) is a systemic disease characterized by necrotizing small-vessel vasculitis of unknown aetiology associated with granulomatous inflammation of the respiratory tract and of renal glomerular and interstitial disease. Patients with renal involvement generally have a worse prognosis than patients with disease localized only to the respiratory tract [1,2], and end-stage renal disease (ESRD) will eventually develop in 1132% [36]. Clinical and morphological evidence of renal involvement is found in approximately 80% of patients with WG [3,4,7]. The characteristic renal lesions are necrotizing glomerulonephritis with extracapillary proliferation. Weak glomerular immune staining may be seen in 1418% of the patients [8,9] and this is within the spectrum of so called pauci-immune glomerulonephritis [10]. Only the infrequent occurrence in renal biopsies of interstitial necrotizing granulomatous inflammation is claimed to distinguish WG from renal lesions seen in other antineutrophil cytoplasmic autoantibodies (ANCA)-associated small-vessel vasculitides [11].
The kidney biopsy is important for the subtyping of rapidly progressive glomerulonephritis, but the prognostic value of the biopsy in kidney disease associated with small-vessel vasculitides is controversial. Some reports have found pathological features such as glomerular necrosis, glomerular sclerosis, and the number of crescents to be of little help in predicting renal outcome [12,13]. Others however, have contended that renal biopsy provides valuable information when evaluating the activity of the renal vasculitis and that it is important for the therapeutic management [1416]. There is no agreement, however, as to which renal lesions are of prognostic value, and this inconsistency makes it difficult to compare the results of clinical and pathological observations from different studies.
The main purpose of the present study was to examine the histopathological changes seen in percutaneous renal biopsies from patients with WG with varying degrees of renal involvement. We also wanted to look for a possible correlation between the morphological variables and the severity of the disease, and to see if these variables were of any value in predicting renal outcome.
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Subjects and methods
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Patients
One hundred and eight patients with WG and active renal disease who were treated in eight hospitals in Norway between 1988 and 1998 were included in this retrospective study. Each of the eight hospitals treated all patients with WG in its catchment area. The total catchment area for the hospitals comprised approximately 2.2 million inhabitants, or about 50% of the total population of Norway. All hospitals had an electronically based register for patient diagnosis, and records from these registers were used to find all patients with the diagnosis of WG. The information was then scrutinized by one of the authors (KA), to confirm the diagnosis.
Ninety-four of the 108 patients (60 males, 34 females) had a percutaneous renal biopsy taken on admission to the hospital and these patients are the basis for this report. The median age of the 94 patients was 54 years (range 1180). Median serum creatinine concentration was 254 µmol/l (range 541440) and 21 (22.3%) of the patients were receiving dialysis therapy at the time of biopsy. The median time from start of symptoms related to WG and biopsy was 5 months (range 0.5214). At the time of biopsy ANCA, as determined by indirect immunofluorescence microscopy [17], were positive in 78 (83.0%) of the patients (71 C-ANCA, 7 P-ANCA). Later in the course of the disease an additional nine patients became ANCA positive, so altogether 87 patients (92.6%) were ANCA positive at some point during the study. The patients were followed for a median of 42.5 months (range 0.5 to 184). Of the 89 patients who survived the acute phase of the disease (3 months after inclusion), 20 (22.5%) developed ESRD, defined as a need for chronic dialysis or renal transplantation.
Clinical diagnosis
The diagnosis of WG was based on the clinical criteria developed by the American College of Rheumatology [18]. As an additional requirement, patients without proven granulomatous inflammation in a biopsy from any tissue, had to be seropositive for ANCA. A clinical diagnosis of active renal disease was defined as signs of active urine sediment, i.e. more than five erythrocytes per high-power field (magnification: x400), or erythrocyte or granular casts. Definitions for the terms remission and relapse are described elsewhere [5].
Renal biopsies
The 94 biopsies were sent to and examined at the Norwegian Kidney Register. The biopsies came from a total number of 2507 renal biopsies received from the eight hospitals and 4956 from the whole of Norway during this period. The histopathological examination and the semiquantitative assessment were carried out by an experienced nephropathologist (LB) who had no prior knowledge of the clinical findings or renal function. One to two cores of renal tissue were obtained and the material was fixed in 10% buffered formalin and embedded in paraffin. Three-micrometer-thick sections were stained with haematoxylin and eosin and periodic acid-Schiff (PAS) for light microscopy. Sections from the paraffin embedded material were also examined by immunohistochemistry (PAP method) for deposits of IgG, IgA, IgM, C3, and C1q. The number of glomeruli with extracapillary proliferation (cellular and fibrocellular crescents) and the number of glomeruli with necrosis were expressed as percentages of the number of non-sclerotic glomeruli. The number of globally sclerotic glomeruli and the number of normal glomeruli were expressed as percentages of the total number of glomeruli in the biopsies. Crescentic glomeruli with rupture of Bowman's capsule were also noted. Interstitial oedema and signs of acute tubular damage (ATD) such as necrosis, flattening, and shedding of the tubular epithelial cells, were recorded as dichotomous data (+/-). Acute interstitial nephritis was defined as interstitial infiltration by mononuclear and/or polymorphonuclear leukocytes, focally or diffusely. Changes characterized by infiltrates of mononuclear leukocytes associated with tubular atrophy and interstitial fibrosis were called chronic interstitial nephritis. Subacute interstitial nephritis was a mixture of acute and chronic morphological features. The term nephron loss was used to describe the degree of chronicity in the biopsies as a summary of the following features: the degree of interstitial fibrosis, the degree of tubular atrophy, and the fraction of globally sclerosed glomeruli. Nephron loss and interstitial fibrosis was scored on a four-point scale in the following manner: 0=0%, 1<25%, 2=2550% and 3>50%. Vasculitis was defined as infiltration of inflammatory cells within and around the vessel wall of arteries, arterioles, or capillaries with or without fibrinoid necrosis. The morphological minimum criteria for benign nephrosclerosis were arteriolosclerosis associated with tubulointerstitial scarring. Granulomatous inflammation was defined as an accumulation of epithelioid histocytes with or without multinucleated giant cells. The location was specified as interstitial, vascular, or related to glomeruli. The term granulomatous reaction was defined as a destruction of the glomerulus with an accumulation of epithelioid cells and/or giant cells [19].
Fourteen patients had a second renal biopsy taken at a later date, and these were examined and compared to the initial biopsy. The mean number of glomeruli in the 94 first biopsies was 12.3, median 10 (range 450). The 14 rebiopsies had a mean of 14.1 glomeruli, median 13 (range 423).
Laboratory investigation
The patients were included in the study at the time of the first kidney biopsy. Serum creatinine was used as an estimate of glomerular filtration rate and recorded at inclusion, at 8 weeks, and after 1 year. For patients on dialysis therapy, serum creatinine was arbitrarily set to 600 µmol/l.
Treatment
At the time of biopsy a total of 29 patients (30.9%) were receiving immunomodulating therapy. Nineteen patients (20.2%) were receiving corticosteroids alone, eight patients (8.5%) were receiving corticosteroids in combination with oral or intravenous cyclophosphamide, and two patients (2.1%) were receiving corticosteroids plus azathioprine. Duration of therapy at the time of biopsy was less than 3 days for 15 (51.7%) of the 29 patients receiving treatment. Sixty-five patients (69.1%) were receiving no specific treatment for WG at the time of biopsy. Following biopsy, therapy consisted of intravenous or oral cyclophosphamide in combination with corticosteroids for 88 (93.6%) of the patients and corticosteroids and azathioprine for five (5.3%). One patient died before treatment was instituted. The treatment protocol included the use of cytotoxic agents (azathioprine or cyclophosphamide) for 1 year following complete remission, after which the drugs were slowly tapered. In the event of a relapse, induction therapy with cyclophosphamide and corticosteroids was reinstituted.
Statistical analysis
Spearman's rank correlation coefficient (
) was used to test a possible association between the percentage of normal glomeruli, glomeruli with necrosis, and glomeruli with cellular and fibrocellular crescents and serum creatinine at the time biopsy, at 8 weeks and at 1 year follow-up. A non-parametric one-way analysis of variance (ANOVA) (KruskalWallis test) was employed to evaluate the association between serum creatinine and histopathological findings when these were expressed on a 4-point scale. A MannWhitney U-test was used when the findings were expressed as dichotomous values. Multiple linear regression was used to see if selected histological variables had an influence on serum creatinine, and with Cox's proportional hazard model we investigated whether histological features were significantly associated with the development of ESRD. Wilcoxon matched-pairs signed-rank sum test was used to make paired comparisons between morphological features when a follow-up biopsy was performed. As the KruskalWallis calculations involved multiple (6) comparisons using the same outcome variable (serum creatinine), the level of significance was defined as P<0.008 according to the Bonferroni method [20]. For the rest of the analyses the significance was defined as P<0.05. All tests were two-tailed.
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Results
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Focal segmental necrotizing glomerulonephritis was present in 80 patients (85.1%) and varying degrees of extracapillary proliferation (crescents) were seen in 86 patients (91.5%). The percentage of glomeruli with crescents divided into five categories is depicted in Figure 1
. Fifty-four (57.4%) of the patients had crescents in 50% or more of the glomeruli and could be classified as having crescentic glomerulonephritis according to the WHO criteria [21]. In 23 (26.7%) of the patients with extracapillary proliferation all crescents were segmental, involving <50% of the circumference of Bowman's capsule (BC) and in 63 (73.3%) there were varying numbers of glomeruli with crescents involving most of the circumference of BC. Rupture of BC was observed in 65 (75.6%) of biopsies from patients with crescentic glomeruli, and in 35 (40.7%) of the patients more than 50% of the affected glomeruli had rupture of the BC. Eight (8.5%) of the 94 patients had extracapillary proliferation but no glomerular necrosis and six (6.4%) had neither glomerular necrosis nor crescents. The median serum creatinine concentration in these six patients was 114 µmol/l (range 90304) and median 24-h proteinuria was 1.7 g (range 0.72.9). Five of the six patients were ANCA positive. In two patients the biopsy showed vasculitis and in one biopsy there were changes consistent with an interstitial granuloma, most probably related to a vessel.

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Fig. 1. The number of patients with varying degrees of glomeruli with crescents in renal biopsies from 94 patients with Wegener's granulomatosis and renal involvement.
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Vasculitis was demonstrated in 14 patients (14.9%). Three biopsies (3.2%) showed aggregates of epithelioid histocytes close to destroyed glomeruli, consistent with granulomatous reactions. Benign nephrosclerosis was present in 15 (16.0%) of the biopsies. All but one of the 94 biopsies (98.9%) showed some degree of interstitial or tubular involvement (Table 1
). The only biopsy with no visible tubulointerstitial involvement was from a 45-year-old woman with a normal serum creatinine (64 µmol/l), proteinuria of 0.5 g/day, and granular and erythrocyte casts seen on urine microscopy, who had received prednisolone (75 mg/day) for 5 days prior to biopsy. Eleven per cent of the glomeruli in her biopsy contained cellular crescents.
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Table 1. Tubulointerstitial involvement and features of chronicity in renal biopsies from 94 patients with Wegener's granulomatosis and active renal disease
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Table 2
depicts some biochemical and morphological patterns in seven biopsies from patients with normal serum creatinine and normal or low urinary protein excretion. All biopsies showed varying degrees of extracapillary proliferation involving 1167% of glomeruli and all but one had glomerular necrosis.
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Table 2. Morphological and biochemical features in seven patients with serum creatinine 100 µmol/l and proteinuria 0.5 g/24 h
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Immunohistochemistry was performed in 93 biopsies and 26 (28.0%) had some glomerular positivity for one or more immunoglobulins or complement factors, the dominating immunoglobulin being IgM and the dominating complement factor C3 (Table 3
). The distribution was mainly focal and segmental with an irregular, partly linear and partly granular pattern. The staining was weak and in most cases probably represented passive trapping in areas of injury. The exception was two cases with granular IgA positivity showing a distinct mesangial distribution. The clinical and histological features of the two patients with IgA positivity are shown in Table 4
. Positive staining for immunoglobulin or complement in non-glomerular vessels was demonstrated in 10 patients (10.8%). The deposits were IgG in two patients, the rest being IgM, C3, and C1q.
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Table 4. Clinical and morphological features in two patients with Wegener's granulomatosis and positive staining for IgA in renal biopsies
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There was a significant positive correlation between the percentage of crescents in the biopsies and serum creatinine at the time of biopsy (
=0.52, P=0.0004), at 8 weeks (
=0.35, P=0.001), and at 1 year (
=0.25, P=0.024). There was also a significant correlation between the percentage of glomeruli with necrosis and initial serum creatinine (
=0.36, P=0.002), but not serum creatinine at 8 weeks or 1 year. The percentage of normal glomeruli correlated inversely with initial serum creatinine (
=-0.55, P=0.0003), serum creatinine at 8 weeks (
=-0.44, P=0.0004), and at 1 year (
=-0.39, P=0.001). The strongest relation between serum creatinine and the percentage of crescents and between serum creatinine and the percentage of normal glomeruli, was described by a non-linear model (exponential) R2 being 0.304 and 0.324 respectively (Figure 2
). There was no significant correlation between serum creatinine and the percentage of totally sclerotic glomeruli or the fraction of glomeruli with disruption of Bowman's capsule. Initial serum creatinine concentration was significantly higher in patients with signs of acute tubular damage (ATD). The median value of serum creatinine at the time of biopsy was 394 µmol/l (range 901440) for patients with ATD compared to 159 µmol/l (range 641102) for patients without ATD (P=0.0003). When patients with any degree of interstitial infiltrates were grouped together, they had significantly higher serum creatinine concentration at biopsy than patients without interstitial infiltrates, median values being 304 µmol/l (range 801440) and 99 µmol/l (range 64604) respectively (P=0.001). One year after biopsy the difference was also significant (P=0.006). Serum creatinine did not differ between the three groups with varying degrees of interstitial infiltrates. There was no significant correlation between serum creatinine at any time and the degree of interstitial fibrosis or nephron loss.

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Fig. 2. Serum creatinine displayed (A) as a function of the percentage of normal glomeruli and (B) as a function of the percentage of glomeruli with crescents. Curve regression lines (exponential) are fitted into the plots. R2 for the two lines plotted in (A) and (B) are 0.324 and 0.304 respectively.
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When a multiple linear regression model was employed using the percentage of normal glomeruli, the percentage of glomeruli with crescents, the percentage of glomeruli with necrosis, the presence of acute tubular damage and of interstitial infiltrates as independent variables, only the fraction of normal glomeruli had an significant influence on serum creatinine at biopsy, at 8 weeks and after 1 year.
In a Cox proportional hazard model, only the percentage of normal glomeruli were shown to have a significant independent influence on the development of ESRD (P=0.012).
Fourteen patients had a second renal biopsy after an average of 41.2 (±26.6) months (Table 5
). In seven patients the indication for performing a new biopsy was signs of active vasculitis and five of them had a significant rise in serum creatinine immediately prior to biopsy. For seven patients, the indication was a rising or constantly high serum creatinine without signs of active vasculitis. Following the first biopsy, 13 of the patients were treated with corticosteroids and cyclophosphamide and one (patient no. 4) with corticosteroids and azathioprine. Seven of the patients had at least one relapse between the two biopsies and one patient had a low-grade active (smouldering) disease. Six patients developed ESRD during the observation period. Exept in one patient (no. 3), the degree of chronicity expressed as nephron loss was significantly more pronounced in the second than in the first biopsy, mean (±SD) scores being 2.14 (±1.0) and 0.43 (±0.6) respectively (P=0.001).
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Discussion
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In this study of renal biopsies from 94 patients with WG and active renal disease, segmental glomerular necrosis and extracapillary proliferation were present in 85.1 and 91.5% of the patients respectively, and 99% had some tubulointerstitial involvement. In earlier studies of ANCA-associated vasculitides, renal biopsies have demonstrated segmental necrosis in 98100% and varying degrees of extracapillary proliferation in 8594% [8,10,22]. The fraction of patients with glomerular necrosis is somewhat lower than reported in these studies, but our patients had varying degrees of clinical renal involvement, including 23% with serum creatinine <125 µmol/l (results not shown). It is of interest to note, however, that glomerular necrosis and crescents were seen in seven patients without elevated serum creatinine and with no or only very scant proteinuria. All of these patients had rather extensive haematuria, suggesting that destructive inflammation in glomerular capillaries with bleeding into Bowman's space could be one of the early events in the development of glomerulonephritis in WG. These findings indicate that morphological criteria might be a better method of defining renal involvement in vasculitis than renal functional measurements, and could be of importance in deciding on whether or not aggressive treatment should be initiated. In eight patients, there was crescent formation without concurrent glomerular fibrinoid necrosis. Although this could be a question of how representative the individual biopsy is as well as a question of the number of slides taken from each specimen, it seems somewhat contradictory to the commonly held view that necrosis is the earliest glomerular sign in crescentic glomerulonephritis [23,24]. The prevalence of immune deposits was higher in our study than in most earlier series of patients with ANCA-associated vasculitis [8,10,22], but in a recent report from the European multicentre trials (EUVAS) the prevalence compared well with ours [25]. Except in two patients with diffuse granular deposits of IgA, the staining was of low intensity and focally distributed. It was predominantly IgM, C3, and C1q and thought to be a consequence of passive trapping in the mesangium. There are several studies describing the coexistence of IgA and P-ANCA in rapidly progressive glomerulonephritis [2628], and in one study two out of 100 patients with IgA nephropathy had high titres of IgG anti-myeloperoxidase antibodies in their serum [29]. To our knowledge there have been no prior reports of IgA immune deposits in patients with C-ANCA-positive crescentic glomerulonephritis, although the development of de novo IgA glomerulonephritis in patients during remission from WG has been seen [30]. Both patients described in this study had circulating IgG antibodies to proteinase 3 by ELISA and c-ANCA by indirect immunohistochemistry, making the diagnosis of ANCA-associated crescentic glomerulonephritis superimposed on IgA nephropathy very likely. The fact that the mesangial hypercellularity was very mild in both cases speaks against a diagnosis of crescentic IgA nephritis [31]. The distinction between these two clinical entities is important, as correct and prompt treatment of ANCA-associated glomerulonephritis is crucial for the prognosis of the disease, but there is no clearly indicated treatment of crescentic IgA nephritis [32].
Using a univariate analysis we have found a positive correlation between serum creatinine and the fraction of active glomerular lesions (crescents, necrosis) and a negative correlation between serum creatinine and the fraction of normal glomeruli. These relationships were best described in a non-linear regression model (exponential). A recently published study also found the percentage of normal glomeruli to correlate to renal outcome, but did not find active glomerular lesion to be significantly correlated to the severity of the renal disease [25]. Only 88 of their 154 patients represented WG, the others being microscopic polyangiitis (MPA), idiopathic rapidly progressive glomerulonephritis (iRPGN), and ChurgStrauss syndrome. Renal biopsies in WG may be characterized by active lesions compared to MPA and iRPGN, where chronicity is more predominant [33]. This could indicate that different morphological features correlate to renal function in WG compared to the other clinical entities. As expected, renal function in the acute phase of the disease was also influenced by the presence of interstitial nephritis and acute tubular damage. On a multiple regression analysis, however, only the percentage of normal glomeruli had a significant influence on serum creatinine. The relationship between serum creatinine and glomerular filtration rate (GFR) is described mathematically by a hyperbola, where the steepest rise in serum creatinine comes with GFR <50 ml/min [34]. In the higher ranges of glomerular renal function a decrease GFR is not necessarily followed by a significant increment of serum creatinine. We propose that a study using a more precise estimate of GFR than serum creatinine could shed more light on the relationship between morphology and renal function.
There was a relatively short time span from the first symptoms related to WG and renal biopsy in our patients. Signs of chronicity expressed in terms of nephron loss (tubular atrophy, glomerular sclerosis, and interstitial fibrosis) were therefore rather uncommon in the biopsies and this could be the reason for the lack of prognostic impact of these indices. There was, however, a striking increase in these features in 13 of the 14 repeat biopsies after a mean follow-up of 3.5 years. All of the 14 patients were treated with corticosteroids and immunosuppressant drugs, but this obviously did not stop the development of chronic renal failure in the majority of the patients, seven of whom had one or more relapse and one had a smouldering disease. Furthermore, the follow-up biopsies revealed that eight of the cases still had active glomerular disease and seven had crescentic glomerulonephritis (>50% crescents in the biopsies).
This study displays the wide range of morphological changes seen in renal biopsies from patients with WG. It also points to the fact that even in the absence of obvious clinical renal impairment, renal biopsy may reveal glomerular necrosis and extensive extracapillary proliferation. We have found the percentage of glomeruli with cellular crescents and the percentage of glomeruli with necrosis to correlate significantly with serum creatinine, but the strongest predictor of renal function and of renal prognosis was the fraction of uninjured glomeruli. The correlation is weak, however, and although an early renal biopsy gives valuable information about the degree of renal involvement in WG, it does not seem to be of substantial help in predicting the course of renal function in the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and nephron loss and may be of importance for the choice of further therapy.
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Acknowledgments
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This study was supported by grants from the County of Sør-Trøndelag, The Norwegian Society of Nephrology and Locus of Epidemiology, University of Bergen. We greatly appreciate the technical assistance and valuable comments offered by Dr Sabine Leh, Deparment of Pathology, Haukeland University Hospital and the technical assistance of Else Kismul and Aud Strømme from the Norwegian Kidney Register. The authors would also like to thank Dr Eirik Skogvoll for his advice regarding the statistical analyses.
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Notes
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Correspondence and offprint requests to: Dr Knut Aasarød, Department of Medicine, University Hospital of Trondheim, Olav Kyrres gate 17, N-7006 Trondheim, Norway. 
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Received for publication: 30. 5.00
Revision received 30.11.00.