The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review

For EUVAS (European vasculitis study group)

Kirsten de Groot1,, Dwomoa Adu2 and Caroline O. S. Savage3

1 Department of Nephrology, Medical School Hannover, Germany, 2 Department of Nephrology, Queen Elizabeth Medical Centre, Birmingham, UK and 3 Renal Immunobiology Laboratory, University of Birmingham, Birmingham, UK



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Background. The study aimed at studying efficacy and adverse effects of pulse cyclophosphamide (pCyc) treatment and to compare it to continuous cyclophosphamide (cCyc) for induction of remission in ANCA-associated vasculitides from data in the published literature.

Methods. A Medline search identified 14 studies, containing more than five patients. From the 11 non-randomized studies, data on outcome following pCyc treatment were extracted. Results were given as fraction of the number of evaluable patients. A meta-analysis was performed on the three prospective, randomized controlled trials to compare outcomes concerning remission, relapses, infection, leucopenia, death and renal failure in patients treated with pCyc as opposed to cCyc.

Results. The 11 non-randomized studies comprised 202 patients receiving pCyc. Cyc pulses of 375–1000 mg/sqm/pulse were applied at weekly to monthly intervals with different concomitant prednisolone regimens and variable adjunctive therapy. Complete remission was achieved in 112/191, partial remission in 23/191 evaluable patients. Relapses occurred in 68/135 patients, 40/115 patients were non-responders. Leucopenia, infections, haemorrhagic cystitis, and deaths were rare. The meta-analysis, comprising 143 patients, showed that pCyc compared with cCyc treatment was significantly less likely to fail to induce remission (OR 0.29; 95% CI 0.12–0.73) and had a significantly lower risk of infection (OR 0.45; 95% CI 0.23–0.89) and leucopenia (OR 0.36; 95% CI 0.17–0.78). Relapses occurred slightly, although not statistically significantly, more often under pCyc treatment (OR 1.79; 95% CI 0.85–3.75). There were no differences in end-stage renal failure or deaths between the two regimens.

Conclusions. The currently available, rather sparse data show that pCyc is less toxic than cCyc therapy and is an at least equally potent inductor of remission, but possibly at the expense of a higher relapse rate. The existing data do not give sufficient information on outcomes as time to remission and relapse, irreversible damage or quality of life without which a treatment regimen cannot satisfactorily be evaluated today. A large prospective randomized controlled trial is needed to address these issues and their relative importance.

Keywords: continuous cyclophosphamide; meta-analysis; microscopic polyangiitis; pulse cyclophosphamide; Wegener's granulomatosis



   Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic diseases, although renal limited variants are well described. They are characterized by pauci-immune small vessel vasculitis and a close association with anti-neutrophil cytoplasmic antibodies (ANCA). Improved diagnostic procedures (immunohistochemistry, ANCA serology, CT, and MRI imaging procedures) have contributed to a greater awareness and increased rates of diagnosis of these diseases. The mainstay of treatment for induction of remission, developed at the National Institutes of Health (NIH) [1], has consisted of oral cyclophosphamide (Cyc) at 2 mg/kg/day and oral glucocorticosteroids (GC), starting at 1 mg/kg/day. Cyc is continued for 1 year after remission and GC are tapered to an alternate day regimen and then stopped after a year of treatment. However, there has been increasing awareness of serious treatment-related toxicity and morbidity [2] and relapses have occurred in up to 50% of the patients, often despite ongoing immunosuppression, probably on a tapering regimen [13].

Alternative immunosupressives comprise low-dose methotrexate, which is reserved for patients with good renal function, mycophenolate mofetil, or anti-thymocyte globulin [4]. The latter two drugs are still too experimental to be recommended for routine induction of remission. So, at present the question is still how to use Cyc for induction of remission, not whether to.

Encouraged by the success of a monthly i.v. Cyc pulse regimen used in systemic lupus erythematosus, a similar regimen was introduced into the treatment of ANCA-associated vasculitis [5]. It offers the potential advantage of a lower cumulative dosage and the likelihood of lower rates of adverse effects. But these benefits may be achieved at the expense of reduced efficacy for remission induction and increased relapse rates. Despite a number of studies addressing the use of intermittent pulse Cyc (pCyc) for induction of remission in ANCA-associated vasculitis, the existing data have not led to a uniform consensus among therapists as to which regimen to give priority.

This study aimed to collect all published trials in which patients with WG and MPA were treated with Cyc pulses and to analyse these reports to determine the therapeutic value of pCyc treatment for induction of remission. A meta-analysis was performed of the randomized controlled trials that were available, to compare where the existing data on pCyc and cCyc take us concerning remission and relapse rate, risk of infections and leucopenia as well as rate of deaths and renal failure.



   Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Literature search and data extraction
Medline search without time limit was carried out with the following search terms: pCyc and vasculitis, WG or MPA. In addition, the reference lists of identified papers and also of previous reviews were searched. Ninety-two citations were found. Papers concerning non-ANCA-associated vasculitides were discarded, as were reports that contained less than five patients with the diseases under study (WG and/or MPA) and reports of which an English translation was not available.

For the analysis of the non-randomized studies, using pCyc treatment, data concerning design of pCyc regimen, rate of remissions, relapses, non-responders, infections, leucopenia, haemorrhagic cystitis, and deaths were extracted, if reported on in the studies. Results are given as percentage of the number of evaluable patients.

Meta-analysis
We analysed data from the three published randomized controlled trials, on which a full length article was available, to compare the effectiveness of intermittent vs continuous Cyc in the treatment of WG and MPA. The outcome measures were remission, relapses, infection, leucopenia, death, and renal failure.

Criteria for included studies
The trials satisfied the following criteria: (i) all patients had clinical or biopsy evidence of WG or MPA, (ii) treatment was assigned randomly, (iii) the concurrent control group in each study received cCyc and GC, and (iv) the experimental group received pCyc with GC.

Each study was examined by two investigators (KdG and DA) and the following recorded: (i) clinical evidence of WG or MPA, (ii) pathological or serological evidence of disease, (iii) method of randomization, (iv) treatment in both arms of the study, and (v) outcome in terms of remission, relapses, infection, leucopenia, death and renal failure.

The quality of included studies was examined from the methods of diagnosis of WG or MPA and the methods of randomization. Details of the treatment given and its duration were recorded.

Outcome measures and statistics
Meta-analysis was performed using Review Manager 3.1 software (update Software, Oxford). The odds ratio (OR) and the 95% confidence interval (CI) for each outcome were calculated for each trial using the assumption free model [6]. The summary odds ratio of all trials and the 95% CIs were calculated.



   Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Altogether 14 studies were found, that were published between 1990 and 1999, and which fulfilled the above criteria. Of those, three were prospective, unblinded, randomized controlled studies, containing >=50 patients each, and 11 were non-randomized, mostly uncontrolled and retrospective studies. The latter category included two abstracts, of which no full length paper was available.

Because of the heterogeneity of the studies with respect to prospective vs retrospective, controlled vs uncontrolled design, disease entities included, choice of endpoint and outcome measures and treatment regimens, the initial intention to perform a formal meta-analysis on all studies could only be carried out for the three randomized controlled trials.

Therefore, in the following, data from non-randomized and randomized studies will be analysed and discussed separately.

A stratification of results concerning disease entities (WG and MPA) was not possible, as the papers mostly did not present the results for WG and MPA separately.

Non-randomized trials
The 11 non-randomized, mostly uncontrolled studies listed in Table 1Go comprised 202 patients with WG, MPA or their renal limited variant who were treated with a pCyc regimen for induction of remission after initial diagnosis or a relapse of their vasculitis. Consequently, pCyc was not always the first immunosuppressive therapy the patient had encountered. Some patients received pCyc because they could not tolerate oral cCyc [e.g. refs 7,8]. In one study [9] a clearcut distinction could not been made between what is defined today as WG, MPA and classical polyarteritis nodosa, so that all patients with these diagnoses under pCyc were included in this assessment. In another study [8] a further 21 patients received pCyc treatment for maintenance of remission. Four studies also report on non-randomized, unmatched control patients that were treated with cCyc [912].


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Table 1. Non-randomized studies using pCyc for induction of remission in WG or MPA, some with retrospective control patients on oral cCyc

 
Within these studies the pCyc regimens varied considerably in dose per Cyc pulse, time between pulses and duration of the treatment (Table 2Go). In summary, doses between 375 and 1000 mg/sqm/pulse were applied at weekly to monthly intervals over a period of 6 months to over a year. Some regimens used pCyc treatment at intervals of 2–3 months for maintenance, after remission was achieved [7,13,14]. The concomitant GC regimen was also not uniform. A proportion of patients initially received 1–3 i.v. pulses of methylprednisolone (MeP). Almost all patients were placed on continuous GC medication starting with around 1 mg/kg of prednisolone equivalent, seldom less [8,15], and doses were tapered according to disease activity. Adjunctive therapy, performed only sporadically, comprised mesna, trimethoprim/ sulfamethoxazole for prophylaxis of pneumocystis carinii pneumonia, as well as additional plasma exchange and/or i.v. MeP pulses in cases of progressive disease.


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Table 2. Treatment regimens in 11 small, non-randomized pilot studies, using pCyc

 
Complete remission was achieved in 112/191 (58.6%) evaluable patients receiving pCyc. One study [9] did not present figures concerning this question. Partial remission was achieved in a further 23/191 (12.0%) patients. Of these 135 patients who achieved some degree of remission, at least 68 patients (50.4%) relapsed, mostly while still receiving pCyc within the first year of therapy, again complete data were not available for evaluating relapse rates. Additionally, at least 40/115 (34.8%) patients were classified as non-responders, denoting patients that suffered from progressive disease during pCyc treatment without ever entering partial or complete remission under this medication. The efficacy of pCyc treatment to prevent end-stage renal failure could not be assessed, because only one study presented sufficient data for the disease entities under study. In this study [11], pCyc treatment enabled three out of four initially dialysis dependent patients to recover an independent renal function.

Of 167 evaluable patients, 20 experienced infectious complications (12.0%), comprising several episodes of pneumonia due to various pathogens, bacterial septicaemia and one case each of pyelonephritis and tuberculous adnexitis. No case of Pneumocystis carinii pneumonia was reported after pCyc, although only three studies reported on the use of P. carinii pneumonia prophylaxis. Out of 105 patients that could be evaluated from four studies, nine experienced leucocytopenia, of which seven patients had mild and uncomplicated leucocytopenia after receiving pCyc at 2 weekly intervals [13], and two patients, receiving pCyc at monthly intervals, had subsequent infectious complications [7]. Out of 146 patients for evaluation, three (2.1%) were reported to have developed a haemorrhagic cystitis during pCyc treatment, one of whom had already had an episode of haemorrhagic cystitis following earlier cCyc treatment. Five of 119 patients that could be evaluated (4.2%) treated with pCyc died from disease or pCyc treatment-related causes during the observation periods of the respective studies.

From the four studies that reported data on patients receiving cCyc (non-randomized, retrospectively assembled control groups), one found no difference in patient survival between pCyc and cCyc treatment [9]; another two found equal efficacy with both treatment modalities concerning regression of disease, with fewer side effects after pCyc treatment [11,12]; the fourth reported that with pCyc therapy serious disease complications or deaths occurred significantly earlier than with cCyc therapy [10].

Meta-analysis of randomized controlled studies
Three prospective, unblinded, randomized controlled trials were found [1618]. Table 3Go presents data on treatment regimens of these three trials.


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Table 3. Treatment regimens in three randomized controlled studies comparing pCyc vs cCyc in ANCA-associated vasculitis

 
Of these, 143 patients were included into the meta-analysis [1618], comprising 101 patients with WG and 42 patients with MPA. The eight patients with polyarteritis nodosa in Adu's cohort [16] were excluded from the meta-analysis.

In all three randomized controlled studies, diagnosis of WG and MPA was established by typical clinical features and the histological evidence of necrotizing vasculitis and/or granulomatous inflammation and/ or segmental necrotizing glomerulonephritis. All but 16 patients were ANCA positive by indirect immunofluorescence and/or ELISA. Randomization was done by computer-generated random numbers in one study [16], in the other two studies no details on the randomization process were provided.

Analysis of the three randomized controlled trials showed (Figures 1aGo–fGo) that pCyc was significantly less likely to fail to induce remission than cCyc (OR 0.29; CI 0.12–0.73). Furthemore, patients treated with pCyc when compared with patients on cCyc had a significantly lower risk of infection (OR 0.45; 95% CI 0.23–0.89) and of leucopenia (OR 0.36; 95% CI 0.17–0.78). As related to the number of achieved remissions, relapses occurred more frequently under pCyc; however, this failed to reach statistical significance (OR 1.79; 95% CI 0.85–3.75).



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Fig. 1. OR and 95% confidence intervals for six different outcome parameters (a–f) from three different randomized controlled studies comparing pulse vs cCyc treatment in ANCA-associated vasculitis. The solid square denotes the OR of an event in an individual study and the horizontal line its 95% confidence interval (95% CI). The black diamond represents the summary odds ratio of all three trials and the 95% confidence interval. Pulse Cyc, pulse cyclophosphamide therapy; Cont. Cyc, continuous cyclophosphamide therapy (control); n, affected patients, N, total number of patients in the respective limb; n.s., not significant.

 
There were no differences in end-stage renal failure (OR 1.29; 95% CI 0.51–3.25) or deaths (OR 0.80; 95% CI 0.34–1.86).

Two of the randomized controlled studies report on the cCyc dose in both limbs [17,18]. Treatment with pCyc resulted in a significantly lower cumulative Cyc dose compared to cCyc treatment (mean doses: 27.8 vs 31.1 g (P<0.001); and 16.4 vs 38.4 g (P<0.001), respectively) in both studies.



   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Non-randomized studies
Between 1990 and 1999 there were 11 non-randomized, mostly retrospective uncontrolled studies, including five or more patients that were performed to assess the efficacy of pCyc treatment in systemic vasculitis. Altogether 413 patients were involved; the majority of them comprised WG, the rest a mixture of Churg Strauss syndrome, classical polyarteritis nodosa, MPA, idiopathic crescentic glomerulonephritis, and collagen vascular disease. Two hundred and two patients with generalized WG or MPA were treated with pCyc treatment for induction of remission after initial diagnosis or relapse.

When trying to analyse these studies to ascertain major outcome criteria (remission, relapse rate, and deaths), several problems are encountered that preclude unqualified statements. (i) Some studies comprise different disease entities, that either would have been classified differently today (e.g. polyarteritis nodosa group comprising patients with MPA and classical polyarteritis nodosa [9]) or that have different pathogenetic backgrounds and probably also different prognosis (polyarteritis nodosa and ANCA-associated vasculitides), but their outcome has not been assessed separately in the studies. A different pattern of involved organs may also influence the outcome, as one could hypothesize that the more frequently involvement of the kidney occurs, the worse is the prognosis of the affected cohort (e.g. 100% of patients in Falk's report [9] had glomerulonephritis vs only 40% of patients at the beginning of the study in Reinhold–Keller's [8] cohort). (ii) The pCyc and concomitant GC regimens are very variable in dose, intervals between pulses and overall duration of treatment, as well as the point at which maintenance treatment was commenced and type of maintenance therapy, ranging from nothing via azathioprine to pCyc at longer intervals. Adjunctive therapies, being used inconsistently in the presented trials, may affect remission and relapse rates as well as the rate of adverse effects (especially infections and haemorrhagic cystitis) and therefore influence almost any outcome parameter. (iii) The definitions of response to treatment, remission (partial or complete) and relapse vary between the studies. (iv) Length of follow-up is very variable, if reported at all, which can considerably influence the given relapse and death rate.

Despite all these drawbacks, some broad conclusions can be reached. First, pCyc treatment can induce complete or partial remission in about 70% of the cases within 3–6 months. Second, about half of these responders will relapse, very often within the first year of therapy, while still receiving pCyc treatment, probably at increasing intervals. Third, while some reports are extremely sceptical about the possibility of achieving sustained remission with a pCyc regimen [7,10,15], the outcome in patient cohorts that were treated with pCyc at intervals shorter than a month (e.g. every 2 weeks [13] or weekly [19] suggested induction of remission rates between 80 and 90% could be achieved. Fourth, adverse drug effects were unusual with pCyc and the parameters ‘severe cytopenia’, ‘infectious complications’, ‘haemorrhagic cystitis’ and ‘treatment- or disease-related deaths’ appeared to occur much less frequently than described after cCyc treatment by Hoffman et al. [2].

Out of the four studies that presented data on a non-randomized retrospectively assembled control patient cohort on cCyc, three reported equal efficacy from pCyc as compared to cCyc, whereas one claimed early disease complications with pCyc that necessitated a switch to cCyc [10]. In three trials lower rates of side effects were seen after pCyc treatment. In the trial by Nachman [12], patients receiving pCyc were treated for considerably shorter periods than patients receiving cCyc (6.9 vs 10.7 months, P<0.004). Whether this accounts for the lower rate of side effects with pCyc remains unclear. The data from these non-randomized controlled trials have to be interpreted with caution as we have no data to confirm that the patients’ cohorts in the two limbs were comparable for disease extent or activity.

Meta-analysis of randomized controlled studies
The meta-analysis demonstrates that in patients with WG or MPA, pCyc is more effective than cCyc in inducing remissions but is less effective in preventing relapses and is accompanied by a significantly lower risk of infections and leucopenia. There is no difference in end-stage renal failure and deaths between the two treatment regimens. As was expected, cumulative Cyc dose was significantly lower with pulse treatment than with cCyc therapy, as judged from two out of the three trials.

Extrapolating from the non-randomized studies discussed previously, the higher remission induction rate and the only slightly and insignificantly higher relapse rate with pCyc when compared with cCyc was unexpected. One might want to argue, that this may have been in part due to the fact that in the study of Adu et al. pulses of MeP or of prednisolone were given together with pCyc; however, these steroid pulses were in place of daily oral prednisolone. Furthermore, in all three studies there was a trend to a higher remission induction rate with pCyc treatment. However, relapse rates with pCyc were lower in Adu's trial and higher in Haubitz's and Guillevin's trial when compared with cCyc.

The remission rate with pCyc (92.7%) in this meta-analysis equals that one achieved with cCyc in a large cohort of WG patients in an uncontrolled study by Hoffman et al. [2]. On the other hand, the relapse rate with pCyc therapy in the meta-analysis is higher than reported by Hoffman for cCyc [2]. So, if the efficacy of a treatment regimen is assessed by a combination of remission and relapse rate, the meta-analysis still does not solve the efficacy issue satisfactorily. From the existing studies, there are no quantitative parameters from which to balance the advantage of a higher remission rate and a lower incidence of adverse effects against the possible disadvantage of a higher relapse rate. Furthermore, we have not sufficient data from the randomized controlled studies to indicate the average time to remission or to relapse. The knowledge of the disease free period within the observation period of the patients would contribute to the assessment of the efficacy of a treatment regimen. Other important criteria in the efficacy assessment are the patients’ quality of life and the amount of irreversible damage that is inflicted on patients with one or the other regimen. So, in order to compare the efficacy of treatment regimens today, more outcome parameters than examined in the presented studies are required. At the time, when most of the studies presented here were started, validated scoring systems for the above mentioned parameters were not available.

The advantage of the meta-analysis is that it outweighs criticism that could be directed at each of the three randomized controlled trials separately. None of them contained enough patients to solve the question of efficacy of pCyc in comparison to cCyc, the ‘golden standard’.

However, the power of a meta-analysis depends—in part—on the balance of the trial limbs within the studies used for the analysis. In one trial, the design of a study [18] may have negatively influenced the results of the cCyc arm as regards cytopenia and infections. Cyc in the continuous limb was only withheld when the leucocyte count fell below 1500/µl. This resulted in a high rate of leucopenia and subsequent infections. In contrast, in the pCyc arm the dose of the following pulse was automatically reduced if the nadir from the previous pulse was below 3000 leucocytes/µl. There, the rate of leucopenia and infection was considerably lower in the pCyc limb.

Clearly in these randomized trials of oral Cyc and pCyc there were differences in the doses of Cyc, the severity of disease, the definitions of remission and relapse, the use of adjuvant treatment. Whilst it is unlikely that the size of the difference in risk of any outcome comparing cCyc and pCyc will be of the same magnitude in these different studies, nonetheless it is likely that any effect will tend to point in the same direction assuming that the method of administration of Cyc is of clinical relevance. The greater the number of studies analysed, the less likely that chance results will obscure the direction of a true effect. We only carried out a meta-analysis in three studies because those were the only randomized trials available.

In conclusion, in non-randomized, mostly uncontrolled studies and by meta-analysis of three randomized controlled trials, pCyc treatment for ANCA-associated vasculitides has been shown to be efficacious for induction of remission. The results of the meta-analysis suggest that the remission induction rate under pCyc surpasses that achieved with cCyc and that the rate of adverse effects is lower as compared with a cCyc regimen. However, there is a slightly, though in the analysis of the currently available data not significantly, higher rate of relapse. Shortcomings of the existing trials were: short follow-up periods, variable maintenance of remission regimens, lack of quantitative measures for disease severity, damage, quality of life and disease free time and even despite the approach of meta-analysis, only moderate numbers of treated patients.

Whilst the meta-analysis provided informative data, we conclude that a larger, prospective randomized controlled trial is needed to establish the relative efficacy of cCyc and pCyc including a sufficiently large number of patients to solve the issue of efficacy and relapse rate. We need to know whether a possible higher relapse rate using pCyc treatment is outweighed by a higher remission rate and/or a reduction of side effects and permanent damage, using reproducible semi-quantative scoring systems for outcome parameters. For these purposes a pCyc and cCyc protocol is required that has been developed from all the previous experiences. This was the aim of the European vasculitis study group (EUVAS), designing the CYCLOPS protocol [20], (www.vasculitis.org) as a large prospective, randomized controlled European multicentre trial.



   Appendix
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Members of the EUVAS study group
Austria: Irmgard Neuman; Belgium: Daniel Abramowic, Philippe Madhoun, Jacques Sennesael; Czech Rep.: Jirina Bartunková, Jindrich Lukás, Ivan Rychlik, Vladimir Tesar; Denmark: Birgitte Ravn Juhl, Hans Løkkegaard, Henrik Nielsen, Jørgen Petersen, Niels Rasmussen, Troels Ring, Søren Freiesleben Sørensen, Wladimir Szpirt, Allan Wiik; Finland: Agneta Ekstrand, Carola Grönhagen-Riska; France: Pierre Bataille Vincent Esnault, Loîc Guillevin, Paul Landais, Philippe Lesavre, Francois Lhote, Laure-Héléne Noèl, Philippe Vanhille; Germany: Konrad Andrassy, Olaf Hergesell, Kirsten de Groot, Wolfgang L. Gross, Karen Herlyn, Wilhelm Schmitt, Fokko van der Woude; Greece: John Boletis, Kyriaki A. Boki, D. S. Emmanouel; Ireland: Conleth Feighery; Italy: Franco Ferrario, Gina Gregorini, Renato Alberto Sinico; Lithuania: Jolanta Dadoniené; The Netherlands: Ingeborg Bajema, Jan Bruijn, Chris Hagen, Herbert Hauer, Hans van Houwelingen, Cees Kallenberg, Coen A. Stegeman, Jan Willem Cohen Tervaert, Kees Verburgh; Portugal: Carlos Vasconcelos; Spain: Eduardo Mirapeix, Manel Solé; Sweden: Zdenka Heigl, Erna Pettersson, Kerstin Westman; Switzerland: Carlo Chizzolini; UK: Paul Bacon, Andrew Exley, Gill Gaskin, David Jayne, Raashid Luqmani, Charles Pusey, Caroline Savage.

Associate members: Mexico: Luis Felipe Flores-Suárez; USA: Ulrich Specks.



   Acknowledgments
 
This work was supported by Grant No. BMH4-CT97-2328 (AVERT), European Community Biomed II Programme.



   Notes
 
Correspondence and offprint requests to: Kirsten de Groot, MD, Department of Nephrology, Medical School Hannover, Carl Neuberg Str. 1, D-30625 Hannover, Germany. Email: kirsten{at}de\|[hyphen]\|grot.de Back



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
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Received for publication: 3. 2.01
Revision received 10. 5.01.