Rheumatology

Rheumatology Advance Access originally published online on March 9, 2006
Rheumatology 2006 45(9):1144-1147; doi:10.1093/rheumatology/kel039

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An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period

M. Adler, S. Chambers, C. Edwards, G. Neild¹ and D. Isenberg

Centre for Rheumatology Research, Division of Medicine, University College London, London, UK and ¹Department of Nephrology, Royal Free Hospital NHS Trust, London, UK.

Correspondence to: D. Isenberg, Centre for Rheumatology Research, Division of Medicine, Room 331, 3rd Floor, Windeyer Building, 46 Cleveland Street, London W1T 4JF, UK. E-mail: d.isenberg{at}ucl.ac.uk

	Abstract

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Objectives. Although the prognosis for patients with renal lupus has improved, a small number still progress to renal failure. Studies from the USA have found it difficult to distinguish whether the higher rate of renal failure in African-Americans is due to genetic or socio-economic factors. Our aim was to identify ethnic and other factors in a UK lupus cohort that contribute to renal failure.

Methods. The University College London (UCL) Hospitals lupus cohort of 401 patients (Whites 64%, Blacks 19%), followed since 1978, has 127 patients with renal disease, of whom 21 have gone into renal failure. We determined the characteristics and possible causes of renal failure in this group. Black patients were disproportionately represented in the renal failure group (62% vs 19% for Whites).

Results. Those in the renal failure group had persistently low C3 compared with the renal disease cohort. A high proportion of patients in the renal failure group were felt to be non-adherent to treatment.

Conclusions. Given that health-care for patients in the UK is free at the point of delivery, we postulate that in our cohort genetic factors rather than socio-economic status are likely to be more significant in causing renal failure. However, there may be cultural and other reasons for this, which requires further study.

KEY WORDS: Systemic lupus erythematosus, End-stage renal failure, Ethnicity.

	Introduction

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Patients with lupus nephritis are at substantial risk of developing end-stage renal failure (ESRF), with estimates in the literature of 10–70% after 5 yr [1–3]. Various clinical and demographic factors have been associated with outcome in lupus nephritis, such as World Health Organization (WHO) class of nephritis, the presence or absence of biological markers, treatment regimens, adherence to treatment, and socio-economic status (SES) and ethnicity of the patient [4]. The association between ethnicity, SES and renal outcomes has been a subject of much research, particularly in the USA. It is known from these data that African-Americans are more likely to go into renal failure but it has been hard to determine whether this is because of their ethnicity or for other reasons, notably SES.

In this study, we have determined the number, characteristics and possible causes of ESRF in a large cohort of patients with systemic lupus erythematosus (SLE) (n = 401) followed in the UK at a single centre since 1978. We have compared features of the group as a whole, those with renal involvement, and those who went into ESRF, with particular reference to their ethnic origin. We have further attempted to analyse the compliance of the patients in ESRF in relation to outcome.

	Methods

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Between January 1978 and December 2004, 127 patients with lupus nephritis were identified from the lupus cohort at the Middlesex Hospital. Patients were defined as having lupus nephritis if they had a biopsy consistent with the WHO classification (n = 122) or, in the rare event of them not having a biopsy (n = 5), if there were very strong supporting data implicating renal involvement attributable to SLE, notably combinations of two or more of the following: diastolic blood pressure >90 mmHg requiring diuretic therapy; hypertension; proteinuria >0.5 g/24 h; creatinine clearance <60 ml/min; serum creatinine >124 µmol/l [5], in the absence of any other relevant disease. Any patient with persistent proteinuria (invariably ++ or greater) or haematuria for which no other cause could be found (e.g. urinary tract infection) was biopsied.

Of these 127 patients, 21 developed ESRF, defined for the purpose of this study as requiring dialysis and/or renal transplant. The patients meeting these criteria invariably had a serum creatinine concentration greater than 600 µmmol/l.

Once established in the cohort, patients with lupus were assessed clinically every 2–3 months using the BILAG (British Isles Lupus Assessment Group) system [6] (for the past 20 yr) with urinalysis and measurement of full blood count, urea and electrolytes, DNA binding and C3 levels, measured at every out-patient attendance. Antibodies to double-stranded DNA (dsDNA) were detected by enzyme-linked immunosorbent assay (ELISA). This assay has been routinely used for over 15 yr. Those patients who presented earlier in the ‘lifetime’ of the cohort were tested routinely by a radioimmunoassay, but their stored sera have all been tested by ELISA. The C3 levels have been measured routinely by laser nephelometry for about 20 yr in our hospital. By case note review we determined if there was any influence on outcome by ethnicity, years of education, time of onset to renal failure, biological markers of activity, namely C3 and levels of anti-dsDNA antibodies, and treatment regimen before the onset of renal failure. In addition, the rheumatologist and nephrologists principally in charge of the patients’ care were asked to independently assess whether, in their view, the ESRF patients had been complying with treatment.

Data analysis
The results were analysed using ² tests to make comparisons between the renal lupus cohort (n = 127) and the ESRF cohort (n = 21). An unpaired t-test was used for comparison of the age of lupus diagnosis between those with nephritis and those in ESRF. The Kruskal–Wallis non-parametric analysis of variance test was applied to calculate the P-values in Table 2.

View this table: [in this window] [in a new window]   TABLE 2. Socio-economic, follow-up, and mortality data of Blacks, Whites and Asians with lupus nephritis

 

	Results

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Of the 401 patients in this cohort, 127 had lupus nephritis and 21 of these developed ESRF. Baseline creatinine in all patients who went on to develop lupus nephritis was normal except in two patients who actually presented in acute renal failure. The mean age of ESRF was 33.4 yr (range 17–58) and eight of the 21 patients received a kidney transplant, three of which failed. Table 1 shows the WHO class of nephritis in the renal group as a whole and in those in ESRF. Table 2 illustrates, in more detail, various socio-economic, follow-up and mortality data of Black, White and Asian patients with WHO class III, IV and V renal disease. We have not included patients of Chinese origin or mixed race in the analysis as the numbers are very small. The mean duration of follow-up since diagnosis of SLE was 8.9 yr for Blacks, 15.1 yr for Whites and 14.2 yr for Asians (P<0.001, Blacks compared with the other two groups). There was no statistically significant difference in time from diagnosis of SLE to development of renal involvement in the three groups. There were 19 deaths in the renal lupus cohort as a whole and 12 of the patients in ESRF died, although not all deaths were attributed to SLE alone.

View this table: [in this window] [in a new window]   TABLE 1. WHO class of nephritis

 
The treatment protocols used in the patients with lupus nephritis were standardized as previously published and are not further described here in detail [7], with the exception that in the past 2 yr we have increasingly prescribed mycophenolate mofetil in preference to cyclophosphamide. Nineteen patients who developed ESRF received at least 6 months of azathioprine at an average dose of 2 mg/kg and five had received mycophenolate mofetil up to the maximum tolerated dose, ranging from 2 to 3 g per day. Seventeen of the 21 ESRF patients were treated with at least three infusions of cyclophosphamide, generally 750 mg per infusion.

Only six patients with ESRF had immunoglobulin G (IgG) anticardiolipin antibodies and only one had a positive lupus anticoagulant (data not shown). Table 3 illustrates the differences in ethnicity between the renal and non-renal groups as well as those in ESRF. In the cohort, 44% (33/74) of Blacks developed lupus nephritis whereas only 22% (58/258) of Whites and 47% (18/38) of Asians did. This difference between Blacks and Whites was statistically significant (P = 0.003) but there was no significant difference between Asians and Whites (P = 0.63). Table 4 shows that our Black patients were particularly likely to have lupus nephritis associated with persistently high levels of dsDNA antibody (defined as twice the upper limit of normal on three occasions) and low C3 levels (defined as being below normal on three occasions) and this was statistically significant. Our data also shows that Blacks were also more likely to progress to ESRF (P<0.001) and that, irrespective of ethnicity, once lupus nephritis occurred, low C3 levels were associated with progression to ESRF (P = 0.018). In the lupus nephritis cohort, age at diagnosis of nephritis was not associated with ESRF (P = 0.932) or with persistently raised levels of dsDNA (P = 0.914). The mean time from SLE diagnosis to development of lupus nephritis was 34 months (S.D. 59), whereas for those who progressed to ESRF the mean time from SLE diagnosis to onset of renal involvement was shorter (12.6 months, S.D. 34.5), although this did not quite reach statistical significance (P = 0.067). The age at which lupus was diagnosed did not differ significantly between those with renal disease and those with ESRF (P = 0.932). The mean time from onset of renal involvement to ESRF was 69.6 months and two patients presented in ESRF. Of the 21 patients in ESRF, 14 progressed to ESRF within the first 5 yr from diagnosis of lupus nephritis, and in seven it was more than 5 yr. Adherence to treatment, as judged independently by two physicians, was poor in the ESRF cohort; non-adherence was agreed to be a significant problem in 11 of 21 patients, nine of whom were Black, and in only one case was there a disagreement about compliance between the physicians. There was no difference in the years of education of the Black, White and Asian patients with lupus nephritis. In Table 5 we show the place of origin of our Black patients.

View this table: [in this window] [in a new window]   TABLE 3. Distribution of ethnic groups in the total cohort, lupus nephritis cohort, and end-stage renal failure cohort

 

View this table: [in this window] [in a new window]   TABLE 4. Comparison of serological features in the Black SLE patients compared with the total cohort, with and without renal disease

 

View this table: [in this window] [in a new window]   TABLE 5. Place of origin of Black patients

 

	Discussion

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
To the best of our knowledge this is the first long-term follow-up study of patients with lupus nephritis who have gone into renal failure outside of North America.

African-American patients are known to have more aggressive lupus and renal disease despite treatment with cyclophosphamide [1]. Our data concur with the American findings—the patients progressing to end-stage renal disease were much more likely to be Black than White or Asian. No differences in follow-up of patients from the various ethnic groups were observed in our study. There are several possible explanations for this observation—it may, for example, be due to certain genetic polymorphisms [8], SES or adherence to medical treatment.

There are conflicting data as to whether ethnicity and SES are causally associated with poor outcome, namely ESRF. Dooley et al. [1] studied 89 patients (51 Black, 38 White) with Class IV nephritis treated with cyclophosphamide as part of the Glomerular Disease Collaborative Network. They found that black patients were significantly more likely to develop ESRF (43% of the Black cohort vs 4.5% of the White cohort), and this was independent of age, duration of lupus, blood pressure control and activity/chronicity indices. They concluded that the subset of patients who rapidly progress to ESRF is virtually confined to Black patients; however, SES and patient adherence to treatment were not studied [1].

Some papers have described a difference in SES to account for the racial differences in outcome [9–11], whereas others suggest that the Black race alone is an independent risk [12, 13]. The measurement of SES is complex and depends on education, income and occupation; however, in the USA studies are often limited to medical insurance status, which may not reflect SES. In one study an estimate of household income suggested that SES, but not Black race, independently predicted poor outcome [14]. In a recent study by Barr et al. [15], the roles of SES and race in lupus nephritis was assessed. The primary outcome measure was doubling of serum creatinine and the authors showed that being Black or Hispanic or living in a poor neighbourhood was possibly associated with progressive disease. With adjustment for poverty and health insurance, the relative risk for African-Americans went from 3.5 to 2.7 and was not statistically significant. They therefore concluded that poverty was an independent risk factor for progressive renal disease independent of race.

Other data contradict this, suggesting that the poor outcome in African-Americans is independent of low SES as reflected by household income and availability of medical insurance [16]. Furthermore, no difference was seen in years of education between the three ethnic groups in our study.

It can be argued that SES is more important in the USA than the UK, given that there is unequal access to health-care in the USA. The UK system is free at the point of delivery; hence we postulate that the frequency of renal failure in our Black population is a genetic rather than socio-economic problem. However, there are some caveats to this conclusion: there still may be important social and economic reasons why the Black population in the UK have worse outcomes; for example, health and cultural beliefs, timing of seeking medical attention and adherence to treatment.

Adherence to treatment is difficult to assess, particularly in an out-patient setting. The disadvantages of various methods were highlighted in a recently published review by Osterberg and Blaschke [17]. By independent assessment of two physicians who knew the patients well, we noted a high degree of non-adherence to treatment in our renal failure cohort, although the data for comparison with the non-end-stage nephritis cohort was unavailable. It is notable that of the 11 non-compliant patients, eight were Black, one was Asian, and one each was mixed Asian/Black and White/Black. In a recent UK study of 189 patients with renal lupus, of whom 22 were Afro-Caribbean, it was shown that Afro-Caribbean race, anti-dsDNA antibodies and IgG anticardiolipin antibodies were associated with an increased risk of renal disease, and this was independent of any socio-economic variable used [18]. However, the authors did not study patients in renal failure and therefore did not say whether there would have been any causality with SES or ethnicity.

Could poor outcome relate to initial under treatment? The therapeutic whims of rheumatologists and nephrologists have changed over the 25-yr period of follow up. Our enthusiasm in particular for long courses of intravenous cyclophosphamide has waned considerably, particularly in view of its long-term toxicity. Indeed, a very recent study has shown that mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, and was associated with less toxicity [19]. Studies are currently in progress to determine the most effective strategy for maintaining disease remission. Relatively few of our patients were re-biopsied (n = 11), though in the main azathioprine was only stopped if it was obvious that it was no longer effective or causing side-effects.

A very recent North American study with a large number of Hispanics and African-Americans has shown that these two ethnic groups, as well as other factors (baseline hypertension, raised serum creatinine and high chronicity index on biopsy), are associated with poor outcome in lupus nephritis [20]. However, they did not try to assess the affect of patient compliance on outcome.

We conclude that Blacks with SLE have a significantly poorer outcome with respect to renal involvement than the white population in the UK. Given the diverse socio-economic and cultural background of our black lupus patients (some born in Africa, some in the West Indies, others in the UK), the similar proportions of each group in the cohort as a whole and amongst those in renal failure is notable (Table 5). It seems to us that this observation supports the idea of a significant contribution of genetics to prognosis in renal lupus. Further studies are needed to determine whether race is a truly independent risk factor for poor outcome, or whether social factors remain more important.

	Acknowledgements

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
We are very grateful to Dr Elisabeth Allen for providing the statistical analysis for this paper.

The authors have declared no conflicts of interest.

	References

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 

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Submitted 29 July 2005; revised version accepted 13 January 2006.
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