Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study

Neil Hedger1,, Judith Stevens1, Nick Drey2, Sarah Walker3 and Paul Roderick2

1 Wessex Renal and Transplant Unit, Portsmouth, 2 Health Care Research Unit and 3 Department of Medical Statistics and Computing, University of Southampton, Southampton, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
Background. The Wessex Renal Unit serves a large stable population (2.5 million). Pauci-immune rapidly progressive glomerulonephritis (RPGN) is a frequent cause of acute renal failure requiring admission to our unit (~8%). At a population level, little is known of the epidemiology and outcome of RPGN.

Methods. Between 1 April 1986 and 31 March 1996, 141 cases of biopsy proven pauci-immune RPGN were seen in the Wessex region. The records of 128 patients were reviewed. Median (range) follow-up was 1.8 (0.9–9.64) years from diagnosis.

Results. The incidence of 4 per million was stable throughout the period. No clustering was seen. The diagnosis was made (median, 25th, 75th centile) 78.5 (45, 166) days after symptom onset. Co-morbidity (mostly hypertension) was seen in 47% of patients. Other organs affected were lungs 63%, nose/sinuses 50%, joints 42%, muscle 33%, skin 22% and nervous system 14%. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 73%; cytoplasmic ANCA 34%, peri-nuclear ANCA 26% and undifferentiated 14%. Twenty-seven per cent tested ANCA negative. The differences between the groups were small; time to diagnosis was shorter in the ANCA negative (-ve) group (P=0.02) and there were more airway symptoms in the ANCA positive (+ve) group (P<0.05). All biopsies demonstrated a necrotizing process; crescents were seen in 96% involving (mean±SD) 54±26% of the glomeruli. Creatinine concentration (mean±SD) at diagnosis was 806±540 µmol/l. Treatment followed established immunosuppressive regimens. Initial dialysis was required by 59%, 36% needing long-term dialysis. At 1 year 68% were alive. The need for dialysis (P=0.0004) and age (P=0.004) were poor prognostic markers. Ten per cent were transplanted, graft survival was 90% at 1 year, no recurrence was seen.

Conclusions. This study, looking at a large cohort, has established the incidence and outcome of ANCA +ve and ANCA -ve RPGN in a defined stable population. It stresses the similarities between ANCA +ve and ANCA -ve cases and supports the notion that pauci-immune RPGN is part of a continuum of vasculitic illness. In this series transplantation is a safe option.

Keywords: ANCA; epidemiology; rapidly progressive glomerulonephritis; transplantation; vasculitis



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
The vasculitides are life-threatening conditions whose destructive nature has been recognized for a long time [1]. Their classification has been problematical, leading to a re-appraisal in 1992. The resulting Chapel Hill Consensus [2] stresses the differences between small, medium, and large vessel disease. It confirms that classical polyarteritis nodosa (PAN), which affects large vessels, is a different disease from the medium/small vessel vasculitides such as Wegener's granulomatosis (WG), microscopic polyangiitis (mPA) and Churg–Strauss syndrome (CSS). These frequently affect the kidneys causing a rapidly progressive glomerulonephritis (RPGN) with few immune deposits, hence the term pauci-immune RPGN. This is a necrotizing process associated with crescent formation. Early detection and treatment are essential [3] if permanent damage is to be avoided and the patient kept from chronic dialysis. Specific immunosuppressive regimens have resulted in greatly improved patient and renal survival [4,5].

Neutrophil dysfunction plays a major role in the pathogenesis of these conditions, a concept reinforced by the description of antibodies directed against the neutrophil cytoplasm in 1985, the anti-neutrophil cytoplasmic antibody (ANCA) [6]. ANCA assays are now in routine clinical use. The presence of circulating ANCA is associated with medium and small vessel vasculitis [7], but not PAN.

Little is known of the clinical epidemiology of these conditions. Although rare, pauci-immune RPGN attributed to a vasculitic process accounted for nearly 8% of acute renal failure admissions to our unit during the study period. Previous studies of pauci-immune RPGN (Table 1GoGo) have concentrated on ANCA positive (+ve) cases [4,814,21]. Because of selection bias due to referral patterns most of these studies do not allow derivation of incidence rates. The one that does [15] studied patients presenting to rheumatologists, only a proportion of whom had renal disease.


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Table 1. Summary of studies of pauci-immune RPGN

 
This paper presents information on the incidence, clinical features and outcome of pauci-immune RPGN irrespective of the ANCA status from a defined population over a 10-year period. It compares characteristics and outcomes of ANCA +ve and -ve cases. We also present a group of patients receiving renal transplants with this condition, an area that has received little attention previously.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
We retrospectively reviewed all patients with pauci-immune RPGN who presented to a large regional renal unit over a 10-year period, from April 1986 to April 1996, during which ANCA serology was routinely performed. We defined the catchment area using the 1993 National Renal Review which collected data on the geographical location of all patients accepted onto renal replacement programmes in 1991–1992 in England. The denominator population was the mid-year estimate for the district health authorities in the catchment area taking the mid-years of two 5-year periods, 1986–1991 and 1992–1996, from the Office for National Statistics. It was 3 158 058 for 1991 as the overall 10 year average. The 10 year population increase was only 61 694. The study area was the former Wessex Regional Health Authority and the Chichester District Health Authority.

Case ascertainment was by search of the histology department databases in the two hospitals with nephrologists serving this population. The hospitals are St Mary's Hospital, Portsmouth, which houses the Wessex Renal Unit, and Southampton General Hospital, a teaching hospital without chronic dialysis facilities. We searched for all cases of necrotizing and crescentic glomerulonephritis (NCGN) without significant immune deposits suggesting a RPGN. Cases of lupus nephritis and Henoch–Schönlein nephropathy were therefore excluded.

One hundred and forty one potential cases were identified of which 128 could be studied in detail. Six cases were untraceable, four were lost in a microfilm accident and three may have had their histology reviewed only, the patients not being clinically reviewed in Wessex. The age/sex profile of the missing patients was not significantly different. One hundred and twenty three patients were included in the incidence analysis. Five patients were excluded; four patients came from the Channel Islands and one from Somerset.

Data were collected from hospital records by a single investigator (N.H.) to achieve consistency.

The onset was defined as the start of symptoms suggestive of a vasculitic illness. To prevent confusion between vasculitic symptoms and other conditions co-morbidity was defined as any unrelated chronic illness present for at least 18 months and still active. Age was that given on the day of admission to the renal unit. Time to diagnosis was the time taken from the start of symptoms to reach a definitive diagnosis based on histology and serology. The involvement of other systems was defined as follows: (i) Upper airways: sinusitis, epistaxis, and nasal granuloma; (ii) lower airways: cough, haemoptysis, unexplained dyspnoea, pulmonary infiltrates and/or cavitation; (iii) joints: arthralgia or arthritis; (iv) muscle: myopathy or myalgia; (v) skin: a vasculitic rash; (vi) nerves: peripheral neuropathy and mononeuritis.

ANCAs were assayed by direct immunofluorescence or by ELISA, both validated tests [16]. ANCA serology was further divided after 1988 into the cytoplasmic staining pattern (cANCA) and the peri-nuclear pattern (pANCA).

We defined recurrence as a re-appearance of the vasculitic process demonstrated by a rising creatinine, worsening proteinuria, an active urinary sediment or suggestive symptoms inexplicable by other diseases. Follow-up data were collected for a median of 1.8 years (range 0.9–9.64), the last date alive either being the most recent clinic review or the date of death as given on the death certificate. Three (2%) patients were lost to follow up, having left the region.

Data were analysed using SPSS, survival analysis by Kaplan–Meier and Cox's proportional hazards model. The {chi}2 method and Mann–Whitney test for non-parametric variables tested differences between the ANCA +ve and -ve cases. Student's t-test was used for parametric variables.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
Incidence
The annual average (with 95% confidence intervals) incidence rate for vasculitis with renal involvement in 1986–1996 was 3.9 patients per million (3.3–4.7). The rate was stable over time; the 5-year average rate for 1986–1991 was 3.4 (2.2–4.4) and 4.4 (3.5–5.6) for 1991–1996.

Incidence increased with age, 0.8 (0.4–1.6) for those aged 18–39, 5.2 (3.7–7.1) aged 40–59 and 8.2 (10.3–12.9) over 60 years.

Geographical variation in the overall incidence rate between the district health authorities ranged from 1.4 (0.7–2.6) to 8.7 (4.4–16.7) per million. This was not related to the proximity of a renal unit.



   Admission characteristics
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
These are summarized in Table 2Go.


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Table 2. Admission characteristics of Wessex RPGN cohort

 
Patients were predominantly referred from general medical units in other hospitals 91 (73%), by rheumatologists 11 (9%), respiratory physicians 6 (5%) and general practitioners 17 (13%). Co-morbidity was observed in 60 (47%) patients. Cardiovascular disease was present in 29 (23%), there were 12 (9%) cases of chronic inflammatory disease (five rheumatoid arthritis, three bronchiectasis, two ulcerative colitis, one chronic osteomyelitis of the leg and one of the spine), eight (6%) of respiratory disease, five (4%) patients were hypothyroid. Neoplasia was present in four (3%), all solid tumours. In this group, the male: female ratio was not significant.

Of the 97 (76%) patients with urine output recorded on admission, 52 (41%) patients were oliguric or anuric.

ANCA assay results were positive in 93 patients (73%). Of these, 46 (36%) had the cytoplasmic staining pattern ANCA and 33 (26%) peri-nuclear staining ANCA. Fourteen (11%) patients prior to 1988 had positive ANCA before differentiation was made between cANCA and pANCA. Thirty-five (27%) patients had negative ANCA despite repeat testing. ANCA serology was assessed as strongly positive in 58 (45%), moderately positive in 24 (19%) and weakly positive in 9 patients (7%) (not recorded in two). More recently, as they became routinely available, ANCA sub-sets were looked for in 26 (20%); anti-proteinase 3 was positive in five (4%), anti-myeloperoxidase in eight (6%) and anti-lactoferrin in one patient. No patient was HBsAg positive. Significantly, more cases of co-morbidity were seen in the ANCA +ve group (P=0.03).

Other auto-antibodies were found in 23 patients (18%); rheumatoid factor (RF) in 12 (9%), anti-nuclear antibodies (ANAs) in eight (6%) and one each of gastric parietal call and thyroid. Four (3%) patients were positive for both RF and ANA. Seven (5%) patients had anti-glomerular basement membrane (GBM) antibodies. None were strongly positive. They were proportionately distributed between ANCA +ve and ANCA -ve cases.



   Treatment
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
Most patients received combination therapy, usually prednisolone (intravenous then oral) with cyclophosphamide, which was later changed to azathioprine. Oral prednisolone was given to 123 (92%) patients, i.v. methyl prednisolone to 102 (80%) patients, the median dose being 1.5 g (range 0.5–3 g, given over 3–5 days). Ninety-five (74%) patients received oral cyclophosphamide, at a median dose of 1.5 mg/kg/day (range 0.5–3). Thirty-eight (23%) patients received azathioprine, the median dose being 1.5 mg/kg/day (range 0.5–2), six (5%) receiving azathioprine at the start of their therapy, the remainder after a median (25th, 75th centile) of 69 (37–175) days of cyclophosphamide. Thirty-five (28%) severe cases had plasma exchange six (1–11) times over 10 (1–36) days. Exchange volume was 3 l (2.5–4 l) all figures are given as median (range). One patient received co-trimoxazole for active nasal disease, another i.v. immunoglobulins for severe disease.

Due to concurrent sepsis and/or cardiovascular collapse on arrival in the renal unit, five (4%) patients had no immunosuppression, all died. These were all severely affected cases.



   Prognosis and outcome
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
Figure 1Go charts the progress of the patients after their arrival on the renal unit.



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Fig. 1. Patient progress from day of admission.

 
Fifty (39%) patients needed chronic renal replacement therapy (RRT) as defined by the USRDS. Allowing for death, transplantation and later RRT, this provided 2–3 patients per year for the dialysis programme, 1–2 patients per million population.

There were 18 episodes of recurrence in 14 (11%) patients, nine (7%) of which needed hospitalization for a median of 5 days (range 2–22). The diagnosis was made clinically, supported by rising ANCA titres in 11 episodes, solely clinically in six episodes and in rapidly rising ANCA titres in one only.

Complicating infections occurred in 46 (36%) with a mean of 1.6 episodes per patient (range 1–6), requiring hospital admission for a median of 14 days (range 1–31).

Neutropenia (white cell count <2x109/l) occurred in 44 (34%). Reduction or cessation of immuno suppression was required in all cases, but five (4%) patients died of sepsis.

Figure 2Go shows the Kaplan–Meier survival curves, comparing those needing RRT with those who did not. Overall, 87 patients survived after 1 year (68%) of whom 75 (59%) were alive by the end of the study period. Of the 53 deaths, 18 had a post-mortem. The main cause of death, as registered in the Death Certificate, was: cardiovascular disease in 18 (14%); sepsis in 14 (11%); the underlying vasculitic illness in 11 (9%); gastro-intestinal complications in four (3%); and three (2%) each of neoplasia and miscellaneous.



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Fig. 2 A graph showing patient survival.

 
On multivariate analysis increasing age and the need for dialysis (even for a short period) conferred a poor prognosis (P=0.0004 and P=0.004 respectively). ANCA status, anaemia, number of glomeruli involved, type of treatment, time on dialysis, smoking, additional system involvement, infective episodes and patient source were all not significant.



   Transplants
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
Thirteen (10%) patients received renal transplants. The median time from diagnosis to transplantation was 1.76 years (range 0.73–8.87). Transplanted patients were younger, mean age 51.0 vs 62.0 years (P=0.05). The median follow up post-transplant was 2.61 years (range 0.14–5.45) when the mean±SD serum creatinine concentration was 176.5±105 µmol/l. All transplants took place after 1990, limiting the follow up period in this study. Three of the patients were ANCA –ve (not significant). At 1 year 92% of the patients were alive. One patient died of surgical complications, the other 12 all had functioning grafts. No recurrent disease was seen.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 
This is the largest reported population-based study of pauci-immune RPGN. It is the only one comparing ANCA -ve with ANCA +ve small vessel vasculitis. In contrast to previous studies [4,814,21] we have included all patients from a defined population referred for renal biopsy. The potential limitations of our study are that it was retrospective, the ANCA assay methodology was changing during this time and it was reliant on routine clinical notes.

The aetiology of vasculitis is obscure. Associations with silicone exposure, petrochemicals, parvovirus B19 and arboviruses have been made [20]. Although not designed to do so, and limited by its retrospective nature, we were unable to demonstrate any aetiological features, in particular there were no occupational, geographical or temporal clusters.

Our incidence rate indicates that this is a rare condition. We may have underestimated, as by using strict histological criteria our search method was highly specific but insensitive. Also, we only looked at cases referred to the regional Nephrology service. Cases seen elsewhere may have been undiagnosed and/or not referred. In addition there may have been cases, with mild renal involvement, treated by other specialists that did not receive a renal biopsy.

Our overall figure of 4 cases per million population per year equated to one admission per month. Earlier studies have suggested a rising incidence [15,17] over time. However, in this study the small rise in incidence rate over the 10-year period was not statistically significant.

We saw less recurrence than some studies [3]. This may be explained by the unselected nature of the cases and differences between centres in the immunosuppressive regimes used. Also, compared to some studies [24], our follow-up period was relatively short. Late recurrence is well described in these conditions.

In comparison with other series, our patients had more severe renal failure on referral and were older, whereas the slight male predominance was similar. These differences probably reflect the unselected referral pattern and despite this, and the high proportion needing early dialysis, our survival figures are similar. Estimating the onset was difficult because symptoms started insidiously. Patients were unwell for a median of 11 weeks prior to admission but, reassuringly, were rapidly transferred to the renal unit once renal failure had been diagnosed. Education of general practitioners and physicians about the nature of this rare disease may result in earlier referral and hence a better renal outcome.

The similarities between ANCA +ve and -ve cases were notable. ANCA -ve cases had fewer upper airway symptoms, a shorter prodrome and, possibly, less systemic upset. This suggests three possibilities: (i) our ANCA -ve cases did not have enough time prior to diagnosis to develop an ANCA; (ii) they were truly ANCA negative; (iii) or they had false negative results. As repeat testing, sometimes in different laboratories, was frequent, the last interpretation seems unlikely. The suggestion that ANCA might appear late further clouds the issue of the exact role of ANCA in vasculitic illness [16].

Using a highly sensitive (~100%) radio-immunoassay, anti-GBM antibodies were detected in one ANCA -ve patient and six ANCA +ve patients, a recognized phenomenon [17]. The assay and its specificity are discussed in reference [25]. However, as the clinical picture and immunofluorescence when performed of the renal biopsy was not that of anti-GBM antibody disease in any of the cases studied, the ANCA -ve phenomenon cannot be attributed to miss-diagnosis.

Interestingly, 12 (9%) of our patients had an underlying chronic inflammatory process raising the possibility that this could have been a trigger for the disease. This has been noted [23] but needs to be studied further. All patients in this study had multi-system involvement predominantly with airway involvement, no case of ‘renal limited’ disease was seen. This agrees with previous studies and indicates that pauci-immune RPGN is always part of a multisystem disorder [18,19,22].

Avoidance of dialysis was a major predictor of survival. This confirms the need for early diagnosis and referral [3]. However, late referral to hospital appears normal. When patients are referred late, the more aggressive immunosuppression used and the severity of the underlying vasculitic process may result in more septic and cardiovascular complications [11].

In this centre transplantation of patients with RPGN began in 1990. Those transplanted were younger than the group as a whole. The results were excellent. No recurrence of vasculitis was seen. We believe that this is the largest group reported from a single centre.

This study has advanced the understanding of pauci-immune RPGN at a population level. It confirms the value of a population-based study in defining the clinical epidemiology of important conditions. We have demonstrated the need to treat ANCA -ve and ANCA +ve disease similarly. National prospective studies/registries are needed if we are to gain a clearer understanding of the aetiology, clinical, serological and histological correlations and outcome of these conditions.



   Acknowledgments
 
We thank Dr N. Marley (Queen Alexandra's Hospital, Portsmouth, Hants) and Dr P. Bass (Southampton General Hospital, Southampton, Hants), Consultant Renal Histopathologists, for identifying potential patients through their databases. Especial thanks to Medical Records in Queen Alexandra's Hospital and the Royal South Hants Hospital, Southampton, also to the staff of Renal Outpatients at the Wessex Renal Unit, for helping locate patient's records.



   Notes
 
Correspondence and offprint requests to: N. A. Hedger, Division of Medicine, Royal Hospital Haslar, Gosport, Hampshire PO12 2AA, UK. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Admission characteristics
 Treatment
 Prognosis and outcome
 Transplants
 Discussion
 References
 

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Received for publication: 22. 9.99
Accepted in revised form: 30. 5.00