Outcome in glomerulonephritis due to systemic small vessel vasculitis: effect of functional status and non-vasculitic co-morbidity
Mark A. Little,
Latiff Nazar and
Ken Farrington
Department of Nephrology, Lister Hospital, Stevenage, UK
Correspondence and offprint requests to: Dr Ken Farrington, Lister Hospital, Coreys Mill lane, Stevenage, Herts SG1 4AB, UK. Email: ken.farrington{at}nhs.net
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Abstract
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Background. Previous studies in systemic vasculitis have defined a number of disease-specific factors including histological parameters and clinical vasculitis activity scores as outcome predictors. This study evaluates the previously neglected role of non-vasculitic factors in determining prognosis in this condition.
Methods. We performed a retrospective study of all patients with a diagnosis of small vessel vasculitis (SVV) presenting with renal impairment to our service over a 12-year period.
Results. Eighty-six patients were studied (median age 63.5 years, 64% male). Mean plasma creatinine at presentation was 533 µM (6.3 mg/dl). Forty-seven patients (55%) required immediate dialysis, 21 (45%) recovered renal function on treatment. The presence of crescent fibrosis (P < 0.05) and interstitial fibrosis (P < 0.01) were significantly associated with a failure to recover renal function. There was a trend towards an increased relapse rate in those with a persistently positive ANCA result or a rising titre. Twelve month patient survival was 85.5% and 5-year survival was 63%. Factors independently associated with mortality were Karnofsky performance score at diagnosis (P < 0.00001), intensity of immunosuppressive treatment (P = 0.0007) and vasculitis classification (P = 0.009). Non-vasculitic co-morbidity was not independently associated with mortality. Patients who were, or became after treatment, dialysis-independent had a significant survival advantage (5-year survival 83 vs 42%, P = 0.001).
Conclusions. Non-vasculitic factors, particularly functional status as indicated by the Karnofsky performance score, play a major role in determining prognosis in SVV with renal involvement and should be an integral component of the decision making process when planning therapy, and in comparing outcomes between centres.
Keywords: ANCA; co-morbidity; Karnofsky score; mortality; relapse; small vessel vasculitis
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Introduction
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Systemic small vessel vasculitis (SVV) associated with ANCA is emerging as an important cause of end-stage renal failure (ESRF) that is associated with increasing morbidity and mortality. It is a multi-system disorder that is frequently complicated by extra-renal morbidity and intensive immunosuppressive therapy. While renal failure due to focal necrotizing glomerulonephritis is the principal factor determining long-term survival [1], extra-renal disease, notably pulmonary vasculitis, also plays an important role. As this is frequently a disease of the elderly (median age of patients in studies over the past 10 years was 56), there are often non-vasculitic co-morbidities present [2]. For example, it would not be unusual for these patients to have underlying ischaemic heart disease or cancer, severe infection or another chronic inflammatory condition such as rheumatoid arthritis.
Several observational studies have analysed factors potentially predictive of an adverse outcome in SVV [36]. These studies have concentrated primarily on factors associated with vasculitis per se. These include histological parameters such as tubular atrophy, glomerulosclerosis and degree of crescent formation [6,7], and clinical vasculitis activity scores (e.g. Birmingham vasculitis activity score) [4,5]. Such parameters are now used to stratify patients, estimate prognosis and guide therapy intensity. However, in this elderly group, it is probable that non-vasculitic factors play an equally important role in determining prognosis and it is essential to take these into consideration when planning treatment. This issue has never been addressed.
Therefore, we undertook to study the effect of functional status (as quantified by the Karnofsky score) and non-vasculitic co-morbidity on outcome (mortality, relapse rate and renal function) in a cohort of SVV patients with renal involvement at a single centre.
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Subjects and methods
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Patient population
The Lister Hospital provides nephrology services to a population of 1.2 million people in South East England. We attempted to identify all patients with a diagnosis of SVV with renal involvement between 1990 and 2002. This was achieved by examining renal biopsy archives (all biopsies showing crescentic or focal necrotizing glomerulonephritis) and the Lister renal unit patient management database, Renal Plus (text search using ANCA, vasculitis, cyclophosphamide, crescentic and methylprednisolone). A total of 124 patients were selected in this fashion for detailed database and medical notes review. Of these, the following were excluded: 23 with a diagnosis other than SVV; 12 with incomplete data or lost to follow up; three with SVV with no evidence of renal disease. Therefore, 86 patients remained and these form the basis of this report. Histological data were obtained from biopsy reports.
Clinical data collected included ANCA status at presentation and during follow-up, treatment received (immunosuppressive and dialytic), change in excretory renal function with time, functional status at presentation (as quantified using the Karnofsky performance score), non-vasculitic co-morbidity and details of SVV relapses. Non-vasculitic co-morbidity was defined as the number of additional diagnoses involving major organs other than the kidney that the patient had at the time of presentation, e.g. solid organ cancer = 1, ischaemic heart disease = 1.
Clinical diagnosis of SVV
Disease classification was based on the Chapel Hill consensus conference on the nomenclature of systemic vasculitis. Patients were only included if they had clinical or histological evidence of a glomerulopathy compatible with SVV. Histological analysis of an affected organ was required to confirm diagnosis. The patients were classified as having Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), ChurgStrauss syndrome, renal-limited vasculitis or SVV with circulating anti-glomerular basement membrane antibodies (SVV-GBM). Serum ANCA activity was assessed using indirect immunofluorescence; samples with a positive result were tested using ELISA for anti-myeloperoxidase and anti-proteinase-3 antibodies. We used this titre to monitor serum ANCA activity sequentially.
Relapse was defined as the development of clinical features suggestive of SVV, with or without a rise in ANCA titre, and improvement following escalation of immunosuppressive treatment.
Treatment of SVV
It has been our policy to treat SVV with various combinations of oral prednisolone, i.v. methylprednisolone, oral cyclophosphamide (usually for 3 months), oral azathioprine (as replacement for cyclophosphamide) and, since 1999, mycophenolate mofetil. Plasma exchange was employed in patients with severe renal impairment and fresh lesions on renal biopsy. I.V. immunoglobulin was employed occasionally in those with resistant disease. Co-trimoxazole was used as Pneumocystis prophylaxis in those receiving cyclophosphamide and/or high dose methylprednisolone. For the purpose of survival analysis, treatment intensity was classified as aggressive (any patient receiving >1.5 g of i.v. methylprednisolone, plasma exchange or i.v. immunoglobulin), standard (full 3 month course of cyclophosphamide at a dose of >1 mg/kg/day plus oral prednisolone) or mild (curtailed or no cyclophosphamide treatment). In addition, the effect of total cumulative cycolphosphamide dose was assessed by dividing the patients into tertiles (first, 05.5 g; second, 5.610.5 g and third, >10.5 g).
Histological parameters
For those patients who underwent renal biopsy, data were recorded on the percentage of glomeruli with crescents, chronicity parameters (crescent fibrosis, tubular atrophy and interstitial fibrosis), presence or absence of interstitial nephritis and vascular changes. These were obtained from biopsy reports; the biopsies were not re-examined. The association of histological scoring with outcome was analysed separately from non-histological factors as the patients who were sicker were less likely to be biopsied.
Outcome measures
The primary end-point was death. The cause of death was obtained from the medical notes. In addition, data were collected on the combined end-point of death or ESRF and on the secondary end-point of ESRF. For the purposes of survival analysis, overall survival time was calculated from the onset of clinical features of SVV and survival in patients with ESRF was calculated from the time of commencement of dialysis.
Statistical analysis
Using SPSS 9.0 software, baseline characteristics and associations between treatment intensity and other baseline features were assessed using the
2 square test, ANOVA or t-test as appropriate. KaplanMeier curves were constructed to estimate survival time. Events were censored at the end of follow up if the patient was still alive. Various groups were compared using the log-rank test. In order to assess which factors were independently associated with mortality, a Cox regression analysis was performed using a forward conditional technique. Only those factors associated with a survival difference on KaplanMeier analysis at a significance level of 0.1 or less were included in the regression model. Assumption of proportionality was tested for each variable. In order to identify factors independently associated with ESRF logistic regression was employed, using the absence of discernible renal function at death or last follow-up as a dichotomous variable. The relapse rate was calculated by dividing the number of relapse episodes by the total time for which the group was at risk for relapse. Relapse rates for different groups were compared with the MannWhitney U test and the overall probability of relapse was assessed with the
2 test. A significance level of 0.05 was considered significant.
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Results
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Demographics and baseline clinical characteristics
The median age was 63.5 years (range 17.684.6) and 55 patients (64%) were male. At presentation, mean plasma creatinine was 566 µM [6.3 mg/dl, 95% confidence interval 5.5 (495 µM) to 7.1 (638 µM)] and 47 patients (55%) required dialysis within the first 48 h. The median duration of symptoms prior to diagnosis of SVV was 50 days (range 11002). Renal biopsy was performed in 84% of patients. Of the 14 patients who did not undergo renal biopsy, 10 were felt to be too ill, two proved technically too difficult and two had no reason given. In all of these, alternative tissue was obtained and demonstrated histological evidence of vasculitis. A breakdown of the SVV classification and clinical characteristics at baseline are summarized in Table 1; 39% had MPA, 36% had WG, 20% had renal-limited vasculitis, 3% had AASV-GBM and 2% had ChurgStrauss syndrome. ANCA testing was performed in 83 patients (96.5%); 35 had a C-ANCA pattern (41%), 34 had a P-ANCA pattern (40%), four had an atypical pattern (5%) and 10 were ANCA negative (12%).
Treatment and overall survival (short and long term)
The intensity of treatment used is summarized in Tables 1 and 2. In an analysis of factors associated with treatment intensity, only the presence of pulmonary vasculitis (P < 0.01) was associated with the use of aggressive immunosuppression. Karnofsky score (P = 0.79), the degree of non-vasculitic co-morbidity (P = 0.78), gender (P = 0.65), previous diagnosis of cancer (P = 0.45), SVV type (P = 0.51), the fraction of glomeruli with crescents (P = 0.97) and the presence of chronic changes on biopsy (P = 0.32) were not significantly associated with the intensity of treatment employed.
There were 324.1 patient-years of follow up (mean 3.4, range 0.112.6). Figure 1 illustrates overall unadjusted survival probability. A total of 33 patients (38%) died during follow up, 12 of these within the first year. The leading causes of death were infection (nine patients, 27%), myocardial infarction (six patients, 18%), progressive vasculitis (three patients, 9%) and malignancy (three patients, 9%). Overall 12-month survival was 85.5% and 5-year survival was 63%.

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Fig. 1. KaplanMeier plot indicating overall unadjusted survival probability. Median survival was 6.16 years (95% C.I. 4.38.0) and 5-year survival probability was 64%.
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The factors associated with short-term (12 month) mortality were treatment intensity (P < 0.025) and Karnofsky score (P < 0.0005), with a trend towards increased short-term mortality with increasing age (P = 0.06) and increased non-vasculitic co-morbidity (P = 0.07). These factors remained significantly associated with short-term mortality following multivariate Cox regression analysis (Karnofsky score, P = 0.001; treatment intensity, P < 0.05).
Considering the total period of follow up, there was a higher risk of mortality in those with non-WG/MPA vasculitis (Figure 2), extensive non-vasculitic co-morbidity (Figure 3), in those receiving low level immunosuppression (Figure 4) and in those with lower functional status (Figure 5). Mortality was inversely proportional to cumulative cyclophosphamide dose (5-year survival: 40, 81 and 100% for the first, second and third tertiles respectively, P = 0.02). Many of these factors are inter-related so Cox regression analysis was used to determine which factors were independently associated with an adverse outcome. In addition to the above factors, age and gender were analysed. Factors independently associated with mortality were Karnofsky score at diagnosis (P < 0.00001), intensity of treatment (P = 0.0007) and vasculitis classification (P = 0.009). In this multivariate analysis, once Karnofsky score was added to the model, the severity of non-vasculitic co-morbidity was no longer associated with mortality (P = 0.28). In order to assess whether treatment intensity was a surrogate for co-morbidity, the multivariate analysis was repeated without treatment intensity included. In this model the effect of co-morbidity was unchanged.

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Fig. 2. KaplanMeier plot depicting unadjusted survival probability according to vasculitis classification. The 5-year survival probability was 76, 69.5 and 36.5% for MPA, WG and other vasculitis (renal-limited vasculitis, ChurgStrauss syndrome or SVV-GBM), respectively (P = 0.01).
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Fig. 3. KaplanMeier plot depicting unadjusted survival probability according to the degree of non-vasculitic co-morbidity. The 5-year survival probability was 95, 62 and 27% for zero, one and two or more additional major diagnoses, respectively (P = 0.0002).
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Fig. 4. KaplanMeier plot depicting unadjusted survival probability according to the intensity of induction treatment received. The 5-year survival probability was 82, 73 and 30% for the groups receiving aggressive, standard and mild treatment, respectively (P = 0.002).
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Fig. 5. KaplanMeier plot depicting unadjusted survival probability according to functional status at the time of diagnosis (stratified into tertiles). The 5-year survival probability was 88, 71 and 37.5% for the third, second and first Karnofsky tertiles, respectively (P < 0.00001).
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Renal outcome
The proportion of patients requiring dialysis over time is summarized in Figure 6. Using logistic regression analysis, only Karnofsky score (analysed as either a continuous variable or by quartile) was associated with the development of ESRF (P < 0.001). Overall, 49 patients (57%) became independent of dialysis. These patients had a significant survival advantage (5-year survival 83%, Figure 7) from time of development of symptoms over those who developed ESRF (5-year survival 42%, P = 0.001). Overall median survival from the time of dialysis initiation was 3.2 years and 1- and 3-year survival probabilities on dialysis were 70 and 56%, respectively. Those with ESRF had more extensive co-morbidity than those who were dialysis independent (P < 0.05). However, co-morbidity was not predictive of mortality in those with ESRF (P = 0.69), whereas it was in those without (P < 0.005). In patients with ESRF, only age (P < 0.005) and SVV type (P < 0.005) were significantly associated with mortality.

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Fig. 7. KaplanMeier plot depicting unadjusted survival probability according to whether or not the patient was left with irreversible, dialysis-dependent renal failure. The 5-year survival was 83 and 42% for those becoming dialysis independent and those remaining on dialysis, respectively (P = 0.001).
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Of the 47 who required dialysis, 21 (45%) recovered renal function, although five of these subsequently required dialytic support again. There were no non-histological factors significantly associated with recovery of renal function on univariate analysis. There was a trend towards more recovery with aggressive treatment (probability of recovery of function 55, 54 and 17% for aggressive, standard and mild treatment respectively, P = 0.08). On the other hand, the presence of crescent fibrosis (P < 0.05) and interstitial fibrosis (P < 0.01) were significantly associated with a failure to recover function, whereas percentage crescents, percentage glomerulosclerosis, degree of tubular atrophy and presence of vasculopathy were not. Multivariate analysis using logistic regression found no factors associated with recovery of renal function.
During follow up, the median time spent in hospital was 25.5 days (equivalent to 3.1% of total follow up duration). A total of 27.9% of patients spent >10% and 9.3% spent >50% of their time in hospital following diagnosis of SVV. There was no correlation between time spent in hospital and Karnofsky score, level of co-morbidity, SVV type or age.
Vasculitis relapse
During the period of follow up, there were 23 episodes of relapse of SVV in 16 patients (19%), 17 of which were extra-renal and six of which were renal. The overall relapse rate was 0.08 episodes/patient-year. A comparison was made between those in whom ANCA activity was persistently positive or in whom it rose acutely prior to the relapse (ANCA positive group, n = 29), and those with a negative ANCA test or in whom ANCA activity was absent prior to the relapse (ANCA negative group, n = 34). Of note, in 23 patients, serial ANCA data (>2 measurements) were not available. The relapse rate was lower in the ANCA negative group (0.05 episodes/patient-year vs 0.12 in the ANCA positive group), although this difference was not statistically significant (P = 0.06). Comparing the ANCA negative with the ANCA positive group, the odds ratio of relapse was 0.33 (95% C.I. 0.11.1, P = 0.081). There was no correlation evident between any histological or non-histological parameter and the relapse rate.
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Discussion
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This study reports on the renal and overall outcome in a cohort of 86 patients with glomerulonephritis due to SVV. We have found that factors unrelated to vasculitis were of critical importance in predicting those patients who did poorly. Specifically, functional status, as quantified by Karnofsky score was the most potent predictor of poor outcome; 5-year survival probability was 88% in the highest tertile, whereas it was 37.5% in the lowest tertile. The presence of non-vasculitic co-morbidity also had a strong association with mortality on univariate analysis, although this disappeared on multivariate analysis. In addition, the group without WG/MPA had a worse outcome, as did those who received low-intensity immunosuppression. Similarly, functional status was strongly associated with the development of ESRF. On the other hand, traditional histological parameters (crescent and interstitial fibrosis) were associated with non-recovery of renal function. The vasculitis relapse rate (0.08 episodes/patient-year) was commensurate with previous studies and, as with most other studies, there was a possible association with ANCA titre trend, although this was not clear-cut.
Our study has several limitations. Data were collected retrospectively, although use of a computerized clinical database into which all patients were entered on presentation may have mitigated some of this effect. Renal biopsies were not subjected to independent review, so the effects of the various histological parameters should be interpreted with caution. In addition, we could not estimate accurately the relative effect of vasculitis activity scores, as this information was not recorded in sufficient detail. Therefore, we were unable to perform a direct comparison between the effect on outcome of non-SVV and traditional SVV-associated factors. It will be necessary to assess this prospectively.
Most previous series looking at SVV have included only patients with WG, many without renal disease [1,2,6,8,9]. Of note, a high proportion of patients in our study had severe renal failure at presentation. Mean plasma creatinine was 566 µM (6.3 mg/dl) and 55% of patients needed dialysis. In previous studies, mean creatinine at presentation varied from 180 (2 mg/dl) to 254 µM (2.8 mg/dl). In a study similar to ours reported by Aasarod et al. (although including only WG patients), 2- and 5-year survival was 88 and 74%, respectively [2]. These results are close to our values of 86 and 64%, and in line with other recent case-series and clinical trials [6,8,10]. From these studies, prognostic scores for risk of death and ESRF have been developed that take into account histological parameters and vasculitis activity [4,5,7,11]. However, none of these factors were as closely associated with outcome as functional status was in our study. Therefore, we believe that this should be accounted for when caring for patients with SVV.
The association between functional status and outcome is not surprising and mirrors anecdotal experience in the clinical setting. It is probable that this parameter is a broad surrogate for the aggregate psychological, social and physical burden of disease and the ability of the patient to withstand the consequences of multi-organ injury, immunosuppression and life on dialysis. It is interesting to note that the effect of non-vasculitic co-morbidity on mortality, while powerful when considered in isolation, appeared to be unimportant when controlling for other factors such as age, gender, SVV type and treatment intensity. Functional status and co-morbidity are related; the latter is an important physical component of the former. It is possible that non-physical factors, such as psychological approach and social support have a larger effect on outcome.
In addition, the intensity of immunosuppression used is an important confounding variable. The assessment of a patient as fragile is likely to lead to a gentle treatment regimen. However, we considered this carefully and, in fact, only the presence of pulmonary vasculitis was associated with aggressive therapy. This is not unexpected as this was used as a criterion for instituting plasma exchange. Frail patients (those with low Karnofsky score) were just as likely to receive intensive treatment as robust ones. Given that this was a retrospective study, it is difficult to distinguish between undertreatment of active vasculitis and appropriate limitation of treatment in those with irreversible organ dysfunction. However, those receiving intensive therapy had a better outcome (independent of potential confounders) than those receiving mild therapy. This suggests that the perception of a need to go gently should be tempered with the fact that, untreated, SVV is almost universally fatal.
Mortality in patients with irreversible renal failure was high in our study (32.5% 5-year survival), although this is roughly comparable to the most recent US renal registry data for patients with vasculitis (35% 5-year survival) [12]. In the largest study looking at this issue, there was a 59% 5-year survival, although the criteria for inclusion included acceptance onto a dialysis programme [13]. Our study looked at all patients with renal failure, including some who were deemed unsuitable for long-term dialysis. Most previous studies have analysed survival in vasculitis patients who had been on dialysis for 3 months, thereby over-estimating survival in patients with renal failure.
Previously reported relapse rates have ranged from 0.02 to 0.3 episodes/patient-year [2,3,14,15], although differences in patient population and definition of relapse make comparisons difficult. Because of the observed association between ANCA activity and disease, several studies have assessed whether this non-invasive measure can be used to predict relapse and allow pre-emptive escalation of immunosuppression [3,14,16]. This has produced mixed results and there is currently insufficient evidence to support such an approach. Likewise, in our study, there was a trend towards an increased relapse rate in those with a persistently positive ANCA result or a rising titre. Systemic vasculitis is a multi-factorial disease; it is likely that ANCA interact with poorly defined environmental and genetic factors and therefore are unlikely to provide accurate prediction in isolation.
The incidence of SVV is increasing and our knowledge of pathogenesis is increasing rapidly. The last two decades, with the advent of cytotoxic therapy, have brought greatly increased survival probability and, consequently, the demographics of this population are changing. The median age in the series reported by Fauci et al. in 1983 was 40 [9]; in our study it was 63.5. The effect of this aging on prognostic factors has been studied extensively in other emerging areas of medicine. In caring for patients with brain tumours and other forms of cancer [17], chronic obstructive pulmonary disease [18] and ischaemic heart disease [19,20], functional status has been established as an integral component of the decision tree when planning therapy. This has yet to become established in the SVV field and we believe that it is now imperative to do so. How these non-vasculitic factors interact with vasculitis activity and histological scoring systems will require prospective study.
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Acknowledgments
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The authors wish to acknowledge the assistance of Dr Haroon Hafeez and Ms Barbara Totty, Histopathology manager, Addenbrookes Hospital.
Conflict of interest statement. None declared.
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Received for publication: 10. 6.03
Accepted in revised form: 17. 9.03