Histological and clinical predictors of early and late renal outcome in ANCA-associated vasculitis

Irmgard Neumann1, Renate Kain2, Heinz Regele2, Afschin Soleiman2, Sandra Kandutsch2 and Franz Thomas Meisl1

1 Department of Nephrology, Wilhelminenspital and 2 Department of Clinical Pathology, University of Vienna, Vienna, Austria

Correspondence and offprint requests to: Dr Neumann Irmgard, Wilhelminenspital, Department of Nephrology, Montleartstr. 37, A-1160 Vienna, Austria. Email: irmgard.neumann{at}nep.wil.magwien.gv.at



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Renal involvement remains a major determinant in antineutrophil cytoplasmic autoantibody-associated small vessel vasculitis (AASV). While some patients may develop persistent renal damage, others have a favourable outcome.

Methods. To identify patients at risk for poor renal outcome, we evaluated 95 renal biopsies (67 initial biopsies and 28 repeat biopsies) of 67 patients with AASV for the presence and extent of active (AI) and chronic (CI) lesions, retrospectively. AI, CI, levels of proteinuria and dose of cyclophosphamide (CYC) were related to renal outcome.

Results. Recovery of renal function in patients initially dialysis dependent was associated with a lower CI compared with patients who remained on dialysis (P<0.001), while AI did not differ significantly. In these patients, age <65 years revealed a positive predictive value of 85% for renal function recovery. Patients initially requiring dialysis exhibited a higher AI and CI compared with those who did not. Renal function in long-term follow-up correlated with CI and the amount of proteinuria. This relationship increased with time, exhibiting at 4 years a correlation coefficient of 0.607 for CI (P<0.01) and of 0.775 for proteinuria (P<0.001). Follow-up biopsies showed a more pronounced CI compared with initial biopsies (P<0.001). None of the investigated initial parameters was predictive for renal relapse. However, there was a relationship between dose and duration of CYC and time to relapse. Compared with the initial biopsy, repeat biopsies of eight patients with a creeping serum creatinine in clinical remission showed a decrease of AI (P<0.001) while CI increased rapidly. These patients also had less initial CYC (NS).

Conclusions. These data suggest that in AASV, evaluation of renal histopathology is helpful in predicting early and late renal outcome. Chronicity and proteinuria were the best determinants of poor renal prognosis. Activity may regress under therapy, while chronicity may progress despite treatment. The amount of CYC seems to influence the occurrence of early relapses and renal survival.

Keywords: ANCA; follow-up biopsies; glomerulonephritis; histopathology; prognosis; therapy



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Renal vasculitis is the most common severe manifestation in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis (AASV) as in Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and renal-limited disease (RLD). The hallmark of acute renal injury is pauci-immune necrotizing crescentic glomerulonephritis (NCGN), but chronic lesions may also be seen to various extents even at the time of disease presentation [1]. Renal outcome of patients with AASV may be heterogeneous, in terms of both renal function and the response to therapy. Prognosis is a particularly important issue when the disease process is aggressive, and an effective but potentially toxic immune suppressive regimen has to be established.

About 25–70% of patients with AASV have dialysis-dependent renal failure at the time of the presentation of their disease [2]. Mortality and morbidity are the highest in patients remaining dialysis dependent [2]. High immunosuppression may contribute to treatment-related morbidity and mortality, but how intensive and longstanding immunosuppression should be has not been clearly established for this subgroup [3,4]. Thus, identification of factors that may influence renal prognosis may be helpful for tailoring a more individual treatment regimen and, as a consequence, reduce drug-related morbidity and mortality in selected patients.

Several groups have investigated the impact of renal histopathological findings on renal prognosis with variable results [1,5–8]. However, both data on renal biopsies of patients initially requiring acute dialysis and data on follow-up biopsies are limited [9,10]. Furthermore, the majority of patients included in histopathological studies were recruited from standardized multicentre treatment studies. Thus, renal follow-up in most of the large studies was restricted to the duration of the study protocol, which was 1–2 years [7,8,11]. It is therefore also of interest to what extent renal outcome years after cessation of immunosuppressive therapy may be influenced by initial renal histology or clinical factors such as proteinuria or initial treatment. The combination of cyclophosphamide (CYC) and corticosteroids has been the cornerstone for successful treatment regiments of ANCA-associated NCGN during the last decades. However, the mode of application, the duration and also the individual tolerance of CYC result in different drug exposure that may also affect renal outcome and relapse rate.

The aim of the present retrospective study was to characterize ‘prognostic subgroups’ in order to identify clinical, histological and therapeutic factors that could represent prognostic factors for early and late renal outcome. Therefore, we investigated the extent of active and chronic lesions of 95 renal biopsies of patients with AASV including 24 renal biopsies of patients initially requiring dialysis and 28 follow-up biopsies obtained in a renal relapse but also in remission.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Sixty-seven consecutive patients [37 males, 30 females; mean age 56±15.3 (range 17–80) years] with AASV and newly detected NCGN were studied retrospectively. These patients were referred to our renal unit between 1989 and 2002 due to suspicion of vasculitis, pulmonary–renal syndrome or because of acute renal failure.

Disease definitions were based on the Chapel Hill consensus conference on the nomenclature of systemic vasculitis [12]. Twenty-eight patients were categorized as having WG, 31 as MPA and eight as RLD.

ANCA serology identified cANCA in 34 patients and pANCA in 23 patients, all in the presence of their typical target antigens, proteinase-3 (PR3) and myeloperoxidase (MPO), respectively. Eight patients were ANCA negative, and no ANCAs were available in two patients who were included because of typical pauci-immune NCGN.

All patients had an initial renal biopsy at clinical onset of their renal involvement. Follow-up biopsies were performed exclusively for clinical indications either under suspicion of a renal relapse in the presence of haematuria and an increase of serum creatinine (SCrea) or because of an unexplained creeping SCrea in clinical remission in the absence of haematuria.

Renal remission required the absence of clinically active renal disease including stable or falling SCrea and the absence of significant haematuria. Patients remaining dialysis dependent have been considered as ‘treatment resistant’.

Evaluation of clinical parameters
At the time of renal biopsy, the following clinical parameters were evaluated: SCrea measured at the time of renal biopsy before initiation of immunosuppressive therapy or haemodialysis, and the degree of proteinuria (mg/24 h). SCrea was evaluated every 6 months. For the evaluation of clinical and histological parameters, end-points for renal follow-up were renal relapse, end-stage renal disease (ESRD) requiring dialysis or death.

ANCA serology
Indirect immunofluorescence was performed using antineutrophil antibody slides (INOVA Diagnostics Inc., San Diego, CA) routinely fixed with ethanol and formalin.

Enzyme-linked immunosorbent assay (Wieslab, Lund, Sweden) was performed for antibodies to PR3 and MPO.

Histopathology
Kidney biopsies were fixed in 7.5% buffered formaldehyde and embedded in paraffin. Twenty serial sections were cut from each biopsy and 2–6 sections were mounted per slide. Slides were stained with haematoxylin and eosin (H&E; one slide), periodic acid–Schiff (two slides), methenamine silver (two slides), and Acid Fuchsin Orange G (AFOG) (two slides). The remaining unstained slides were used to perform indirect immunohistochemistry to detect deposition of IgG, IgM, IgA, C3, C1q and fibrinogen using standard techniques (ABC Elite kit, Vector Laboratories).

Scoring of renal biopsies
All biopsies were reviewed and scored independently by two pathologists who were unaware of the ANCA specificity and the clinical presentation, retrospectively.

Based on the standardized scoring system for activity and chronicity developed for lupus nephritis [13], we modified this system with respect to the characteristic lesions in necrotizing and crescentic glomerulonephritis. The morphological changes were assessed as shown in Figure 1. Briefly, the glomeruli, tubules, interstitium and vessels were assessed separately for inflammatory lesions and sclerotic/fibrotic lesions. To assess the exact amount of glomerular lesions, glomeruli were divided into eight segments. Each segment was scored for the presence of necrosis, hypercellularity, increased mesangial matrix and sclerosis. The number of affected eights (a in Figure 1) was used to calculate the percentage of the glomeruli affected by each of the changes. Points were given as follows: 1 point for <20% affected, 2 points for 21–40%, 3 points for 41–60%, 4 points for 61–80% and 5 points for >80%. The presence of cellular crescents was based on examination of serial sections, and the percentage of glomeruli surrounded by total or partial crescents was calculated. Fibrous crescents were counted only when they were partial because circumferential fibrous crescents invariably were part of a totally sclerosed glomerulus. Intracapillary hypercellularity was assessed semi-quantitatively without separating the respective contributions of neutrophils, monocytes and endothelial cells. The extraglomerular changes were assessed semi-quantitatively as indicated in Figure 1. For tubulo-interstitial lesions, <30% of tubules or interstitial area affected was considered as mild (1 point), 31–60% affected as moderate (2 points) and >60% affected as severe (3 points). The results were used to derive the activity and chronicity indices (AI and CI). Numbers of unaffected glomeruli and percentage of scars were noted separately.



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Fig. 1. Evaluation of renal histology. AI = activity index; CI = chronicity index; n = number of glomeruli; a = number of glomerular segments affected by any changes (one segment is defined as an eighth of one glomerulus); m = number of glomerular scars; () amount of maximal points. Points for semi-quantitative assessment were given as follows: 0 = absent; 1 = mild; 2 = moderate; 3 = severe.

 
Data are shown as total AI and total CI and also as a more detailed analysis with respect to inflammatory and sclerotic/fibrotic glomerular, tubulo-interstitial, arterial vessel and granulomatous lesions.

Treatment
Initial therapy included CYC and steroids in all patients. Since this is a retrospective analysis over two decades, treatment regimens have changed within this time period. Therefore, both application modes (oral vs intravenous) and duration of CYC differed inter-individually, resulting in various cumulative dosages of CYC. In addition, patients who poorly tolerated CYC, most of them due to leukopenia, were also included. Thus, it was possible to investigate the impact of various dosages of CYC on renal outcome and on renal histology of follow-up biopsies. Generally, treatment of these patients was based on active renal disease and had not been influenced by the presence or absence of single histological changes.

In all patients, glucocorticosteroids were administered initially as a pulse (bolus of 0.5 g for 3 days) followed by oral prednisolone 1 mg/kg body weight/day tapered down to an alternate-day schedule within 3–5 months when remission was induced. Plasma exchanges were added to CYC and glucocorticosteroids only in individual cases with severe pulmonary haemorrhage. In patients recruited later in the 1990s, when remission had been induced with CYC at 6 months, azathioprine or mycophenolate mofetil was given as remission maintenance therapy.

Statistical analysis
For assessing inter-rater variability concerning AI and CI, Cohen's weighted kappa was calculated [14].

Data are given as means±SD. Student's t-test or ANOVA with the Tukey option were used to compare means as appropriate. A P-value <0.05 was considered to be significant. Comparison between dichotomous variables was evaluated by Fisher's exact test. Spearman's coefficients were used to test correlation.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
To identify patients at risk for poor renal outcome, clinical and histological parameters were evaluated with respect to prognostic groups as shown in Figure 2. In 51 patients, a remission was induced. Out of 24 patients initially requiring dialysis, 10 recovered renal function and went into remission while 14 were treatment resistant and remained on dialysis. Twenty-four patients of the remission group had at least one follow-up biopsy (two patients had two and one patient had three). Sixteen second biopsies were obtained in a renal relapse and eight patients had a biopsy in remission because of a creeping SCrea. Mean renal follow-up including patients with a renal relapse was 260±218.2 weeks. Seven patients progressed to ESRD within a mean follow-up of 209±260.3 weeks. In 22 patients, mean renal follow-up was >5 years.



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Fig. 2. Patient groups.

 
Assessing inter-rater variability revealed a good degree of agreement concerning activity ({kappa} = 0.6, 95% confidence interval 0.48–0.78; P<0.0001) and a moderate degree of agreement concerning chronicity ({kappa} = 0.4 95% confidence interval 0.30–0.54; P<0.0001).

Initially dialysis-dependent patients: clinical and histological characteristics of patients who recovered renal function compared with patients remaining on dialysis (treatment-resistant group)
Patients who initially required dialysis and recovered renal function exhibited a significant lower chronicity compared with those who remained dialysis dependent due to treatment resistance (6±2.0 vs 12±2.8; P<0.001), while activity and SCrea did not differ (Table 1). When calculated for each parameter separately, patients with recovery of renal function showed less segmental glomerular sclerosis (1±0.9 vs 3±1.5, P<0.01), less interstitial fibrosis (1.2±0.6 vs 2±0.8, P<0.05), less tubular atrophy (1.1±0.6 vs 2.1±0.8, P<0.01) and less chronic vascular damage (1.0±0.8 vs 2.2±0.69; P<0.001) compared with dialysis-dependent patients. In addition, a total CI of >10 and/or a glomerular CI of >5 were predictive for dialysis dependence (positive predictive value 100% for each), while a tubulo-interstitial CI of >3 revealed a positive predictive value of 88%. The percentage of normal glomeruli was comparable in both groups. Neither the type of vasculitic disease nor ANCA specificity was a prognostic parameter. Patients who recovered renal function seemed to be somewhat younger, although this was not statistically significant (53±14 vs 58±17, P = 0.495, NS). However, age <65 years revealed a positive predictive value of 81% for renal recovery. In addition, of all organs involved at diagnosis, the best prediction for recovery of renal function was shown for the presence of athralgia, exhibiting a positive predictive value of 70%.


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Table 1. Clinical and histological characteristics of initially dialysis-dependent patients: patients who remained dialysis dependent compared with those who recovered renal function

 
Clinical and histological characteristics of patients initially dialysis dependent compared with those who were not
Patients requiring dialysis at diagnosis exhibited significantly higher activity and chronicity compared with patients who were not dialysis dependent (17±4.7 vs 12±5.7, P<0.01 for AI; 9±3.6 vs 7±3.2; P<0.01 for CI) (Table 2). Also chronic vascular damage was more severe in initially dialysis-dependent patients, while the percentage of normal glomeruli was lower in this patient group (26±23.2 vs 47±29.9; P = 0.05). There was no significant difference with respect to ANCA type or diagnosed disease between both groups. Age >65 years was not predictive for dialysis dependence at diagnosis, exhibiting a positive predictive value of only 48%.


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Table 2. Clinical and histological characteristics of patients initially dialysis dependent compared with those who were not

 
Follow-up biopsies
Follow-up renal biopsies were available in 24 patients and were related to two diagnostic groups. Sixteen biopsies were obtained in a renal relapse (‘relapse group’) and eight were performed because of a creeping SCrea in the absence of clinically active disease (remission–‘creeping Screa group’).

Relapse group
Sixteen patients (24%) suffered at least one renal relapse after a mean follow-up of 45±29.1 months. Of these patients, six had WG, nine had MPA and one had RLD. Seven were cANCA positive, eight were pANCA positive and one was ANCA negative. None of the initial histological or clinical parameters was predictive for renal relapse. CI increased between the first and second biopsy (6±1.7 vs 10±3.4, P<0.001), mainly due to an increase of glomerular sclerosis, while no differences were found for tubulo-interstitial lesions (Table 3), or when calculated for singular histological parameters (data not shown). SCrea, AI and the percentage of normal glomeruli were comparable in both ‘active’ biopsies, the glomerular inflammatory lesions being slightly lower in the relapse group (Table 3). When compared with patients with long-term renal remission, there was a trend for patients of the renal relapse group to have received less initial cumulative CYC for a shorter time (227± 210 vs 336±265 mg/kg body weight, NS; 15±16 vs 22±17 g, NS; 30±29 vs 53±36 weeks, NS). We found a significant association between the time to relapse and both dose (r = 0.613, P<0.05) and duration of CYC (r = 0.525, P<0.05) (Figure 3).


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Table 3. Follow-up biopsies of patients with a renal relapse compared with patients with a creeping SCrea in clinical remission

 


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Fig. 3. Influence of dose of cyclophosphamide (CYC) on time to renal relapse.

 
Third renal biopsies were obtained from three patients with a second renal relapse. These three patients were characterized by a long renal follow-up exceeding 10 years without progression to ESRD, exhibiting only a slight increase of CI in their follow-up biopsies (data not shown).

Remission–‘creeping SCrea’ group
Follow-up biopsies of eight patients with a creeping SCrea in the absence of clinically active disease showed a significant decrease of active lesions (16±5.3 vs 5±3.8; P<0.001). There were no crescents or fibrinoid necrosis present; however, biopsies showed persisting slight intracapillary proliferation (0.3±0.5 vs 0.4±0.5, NS) and mild mesangial cell proliferation (0.6±0.8 vs 0.5±0.8, NS, initial vs follow-up biopsy, respectively). In further analysis, tubulo-interstitial changes such as interstitial oedema, interstitial infiltrate and acute tubular necrosis did not differ between either biopsy, while tubulitis and casts decreased in remission (data not shown). The percentage of normal glomeruli increased in remission and was the highest observed within all groups. CI increased much faster than in the relapse group, exhibiting a comparable increase of CI in a significantly shorter biopsy interval (16±12.1 vs 45±29.1 months, P<0.01; remission vs relapse group, respectively) (Table 3). The more detailed analysis exhibited a significant increase of glomerular sclerosis (1.4±1.5 vs 3.4±1.2, P<0.05) and of tubular atrophy (1.3±0.8 vs 2.3±0.7; P<0.05) between first and second biopsy, while no significant increase was found for interstitial fibrosis (1.3±0.7 vs 1.5±0.9, NS). Although chronic damage of arterial vessels was initially very low, it progressed very rapidly (Table 3). It was noteworthy that patients of this group were significantly younger than patients of the relapse group (42±11 vs 58± 12 years, P<0.01). The creeping SCrea group also had somewhat less cumulative therapy with CYC compared with patients with long-term renal remission and stable renal function (228±123 vs 336±265 mg/kg body weight, NS; 14±8 vs 22±17 g, NS; 32±10 vs 53±36 weeks, NS). Neither type of vasculitic disease nor ANCA specificity (four WG, three MPA, one RLD; five cANCA, two pANCA and one ANCA negative) further characterized this group.

Generally, chronicity at the second biopsy correlated positively with the amount of proteinuria, at onset (r = 0.661, P<0.001) and at the time of the second biopsy (r = 0.474, P<0.05). It has to be noted that all patients with proteinuria were treated with angiotensin-converting enzyme inhibitors and/or angiotensin-1 receptor blockers which may have contributed to the decrease of proteinuria at the time of the second biopsy. Unfavourable renal function at second biopsy was associated with higher proteinuria, a lesser cumulative dosage and a shorter duration of CYC (Table 4). As expected, there was also a positive correlation for AI and CI and an inverse correlation for the percentage of normal glomeruli with renal function at the follow-up biopsy.


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Table 4. Renal function at second biopsy: influence of clinical and histological parameters

 
Remission group: the relationship of initial renal histology and proteinuria to renal function in early and long-term renal follow-up
For early renal outcome at 1 year, total AI and the percentage of normal glomeruli were relevant markers. The more detailed analysis showed positive correlations for both inflammatory and sclerotic glomerular changes, but not for crescents when calculated separately. We found no significant relationship between renal function at 1 year and tubulo-interstitial lesions, even when calculated separately for single histological parameters (data not shown).

For late renal outcome, the best positive correlations were found for total CI, percentage of scars, glomerular sclerosis and the amount of proteinuria, while the percentage of normal glomeruli was inversely correlated. These relationships increased with time, exhibiting the highest coefficients at 4 years (Table 5). When calculated for single histological parameters, positive correlations were also found for tubulo-interstitial infiltration (r = 0.393, P<0.05 and r = 0.405, P<0.05, for 3 and 4 years, respectively) and segmental sclerosis r = 0.527, P<0.001 and r = 0.589, P<0.01, for 3 and 4 years, respectively).


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Table 5. Initial clinical and histological parameters with respect to renal follow-up

 
To test the relationship of proteinuria to renal histology at diagnosis, each histological feature was related to the amount of proteinuria. A positive relationship was found between proteinuria and chronic lesions such as glomerular sclerosis (r = 0.342, P<0.01), mesangial matrix increase (r = 357, P<0.01) and tubular atrophy (r = 0.287, P<0.05). There was also a weak positive correlation of proteinuria with mesangial cell proliferation (r = 0.271, P<0.05), although mesangial cell proliferation was generally low (a maximum of 1+ was observed only in 16 cases, a maximum of 2+ in only three cases).

Patients with progression to ESRD (n = 7; four cANCA positive, two pANCA positive and one ANCA negative) were characterized by a higher proteinuria when compared with patients with stable renal function (3.4±2.7 vs 1.6±2.0 g/24 h, P<0.05). Cumulative CYC dose was lower in this subgroup due to poor tolerance of CYC in three of the seven patients (121±85 vs 336±265 mg/kg body weight, P<0.05; 8±6 vs 22±17 g; P = 0.05).

Clinical and histological features with respect to vasculitic disease and ANCA specificity
Initial SCrea was lower in patients with WG (3.8±3.4) compared with MPA (5.8±3.9, P<0.05) or RLD (7.3±3.8, P<0.05). CI and proteinuria were only slightly higher in MPA and in RLD compared with WG (data not shown).

ANCA-negative patients exhibited the highest entry SCrea, amounting to 7.5±2.7 mg/dl compared with 5.1±3.9 mg/dl in pANCA- and 4.4±3.7 mg/dl in cANCA-positive patients (P<0.05; ANCA negative vs cANCA). ANCA-negative patients also had the highest proteinuria (5.3±5.7 vs 2.3±2.5 vs 1.8± 2.1 g/24 h; ANCA negative vs pANCA vs cANCA, respectively; NS).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study, we analysed histological, clinical and therapeutic factors that could predict early and long-term renal outcome in patients with AASV. This is the first study also evaluating renal biopsies of initially dialysis-dependent patients. In this subgroup, glomerular, tubulo-interstitial and vascular chronicity appeared as key markers for renal function recovery, being significantly higher in patients remaining dialysis dependent compared with those who recovered renal function. Moreover, a total CI of >10 or a glomerular CI of >5 was predictive for dialysis dependence. Neither inflammatory lesions nor the percentage of normal glomeruli in the renal biopsy were helpful in predicting renal recovery. However, age <65 years and the presence of arthralgia at diagnosis revealed as additional parameters, exhibiting a positive predictive value for recovery of renal function of 81 and of 70%, respectively. Initial SCrea has been described as a predictor for long-term renal function [5,11] but it is clearly not helpful in patients on dialysis. Therefore, especially for patients initially requiring acute dialysis, renal biopsy provides not only a diagnostic procedure but also a prognostic procedure that may have therapeutic implications.

In contrast, initial biopsies of dialysis-independent patients responsive to therapy were characterized by a lower total AI, lower total CI and less chronic vascular damage, while the percentage of normal glomeruli was significantly higher when compared with patients initially dialysis dependent.

Data on follow-up biopsies of patients with AASV are limited, especially in clinical remission of the disease. For ethical reasons, we were not able to study follow-up biopsies in patients with remission and stable renal function. However, follow-up biopsies of patients with clinical remission and a creeping Screa were available. When compared with biopsies of the relapse group, second biopsies of the ‘creeping SCrea group’ exhibited a significant decrease of inflammatory lesions and an absence of the hallmark of active glomerulonephritis, i.e. crescents and fibrinoid necrosis. Both groups showed a comparable increase in total CI between initial and follow-up biopsy; however, patients of the ‘creeping SCrea group’ were younger and developed this CI within a significantly shorter time period. Interestingly, the percentage of normal glomeruli was the highest in the ‘creeping SCrea group’. Concomitantly, ongoing tubulo-interstitial inflammation and more proteinuria may have contributed to progressive renal failure in these patients. Chronic lesions at the follow-up biopsy may thus only partly reflect irreversible injury induced during the initial active phase of the disease. It is of note that the ‘creeping SCrea group’ also tended to have less initial CYC compared with patients with stable SCrea in long-term remission. Therefore, it cannot be excluded that higher dosages of CYC would have been mandatory to suppress smoldering disease completely in this subgroup.

Tolerance and the amount of initial immunosuppressive therapy may also have an impact on the occurrence of renal relapse. In this study, patients who experienced a renal relapse had received less initial CYC compared with the remission group. This difference was not significant due to high standard deviations. However, there was a significant relationship between dose and duration of CYC and time to relapse, suggesting that less treatment with CYC carries the risk of early renal relapse. Guillevin et al. found no difference with respect to the induction of remission when using either intravenous pulse or oral CYC; the incidence of relapse, however, was significantly higher in those treated with the dose-sparing pulse regimen compared with oral CYC [15]. Side effects, however, were substantially reduced by administering the drug in intravenous pulses. Thus, in some patients, remission may be induced with lower dosages of CYC. Therefore, the advantage of less toxicity may be counteracted by an unfavourable long-term outcome and a higher relapse rate. Nevertheless, in our relapse group, the lower CYC dose could not be attributed exclusively to the intravenous pulse regimen.

Pronounced chronicity in follow-up biopsies of renal relapses has also been described by other authors [9,10], and an increase of nephron loss has been reported in five biopsies in the absence of active glomerular disease [10]. Hauer et al. also suggested that on average no glomeruli are recruited into the active process of relapse biopsies [9]. In line with these authors, we found a comparable percentage of normal glomeruli in initial and relapse biopsies and an increase of glomerulosclerosis at the second biopsy [9].

In this study, we also analysed late renal outcome after cessation of immunosuppression. Proteinuria and predominantly chronic lesions, such as total CI, percentage of scars and glomerular sclerosis, showed a positive correlation with renal function at 2 and 3 years, while the percentage of normal glomeruli was inversely correlated. These relationships increased during follow-up, exhibiting the highest coefficients at 4 years. The amount of proteinuria could be related to chronic changes rather than to inflammatory lesions. We have reported previously that patients with AASV and proteinuria have a less favourable renal prognosis [16]. Another study reported that in anti-MPO-positive patients, proteinuria at diagnosis was higher in patients who developed chronic renal failure [17]. The predictive power of proteinuria for progressive renal insufficiency has been demonstrated previously in renal disease, also highlighting the importance of reduction of proteinuria by the interruption of the renin–angiotensin system [18]. Angiotensin-converting enzyme inhibitors and/or angiotensin-1 receptor blockers may also have contributed to the decrease of proteinuria at the time of the second biopsy in our patients.

In contrast to long-term renal outcome, renal function at the first year correlated positively with the initial SCrea and the total AI, and inversely with the percentage of normal glomeruli. Analysis of single parameters revealed glomerular inflammatory and sclerotic lesions as markers for renal function at 1 year. Bajema et al. found the percentage of normal glomeruli to be the best predictor for renal outcome at 1 year [7]. In agreement with our data, another study reported a correlation of renal function at 18 months with initial renal function and with glomerulosclerosis [8]. Tubulo-interstitial lesions have also been shown to be predictors of renal function at 18 months and later in the follow-up [7,8,19]. In our study, tubulo-interstitial infiltrates correlated with renal function at 3 years and later.

Histological and clinical evaluation with respect to vasculitic diagnosis showed the highest entry SCrea and more extensive chronic lesions in RLD. Six of eight patients with RLD required acute dialysis at the time of the presentation of the disease; only two of them recovered renal function. However, this might not be due to more aggressive disease, but rather to delayed diagnosis in the absence of extra-renal manifestations.

Data on ANCA subtype and renal prognosis are controversial. Recent studies reported that kidney biopsies from MPO ANCA-positive patients exhibited higher chronicity than biopsies from patients with PR3 ANCA, concluding that patients with MPO ANCA-associated MPA display a more chronic and less active injury in their kidneys at the time of presentation [1,6,20]. In another histological study, no differences were found between patients with anti-MPO or anti-PR3 antibodies [11]. Our findings suggest that the ANCA subtype makes no independent contribution in predicting patient prognosis. Slot et al. reported that progressive renal failure in PR3 ANCA-positive patients is very rare [21]. Although in our ‘creeping SCrea group’ five patients were PR3 positive, in this subgroup renal function may rather reflect a clinical stetting characterized by poor tolerance of the treatment and the higher proteinuria observed than a typical renal follow-up in PR3-positive patients.

In conclusion, renal biopsy remains an important procedure for the evaluation of the severity and extent of renal involvement and for therapeutic decisions. Especially in dialysis-dependent patients, the amount of sclerotic/fibrotic lesions in renal biopsis may indicate treatment response and may, in selected cases, provide a helpful tool in tailoring the immunosuppressive strategy. CI and proteinuria at the time of disease presentation not only represent the current status of renal damage but are also relevant markers for renal outcome several years later. Inflammatory lesions may regress under immunosuppressive therapy, whereas glomerular sclerosis or interstitial fibrosis may progress despite treatment. Although clinical remission may also be induced by lower doses of CYC, intolerance to the drug and less CYC may carry the risk of experiencing an early renal relapse or less control of smoldering renal disease.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 24. 2.04
Accepted in revised form: 1.10.04