Q J Med 1999; 92:211218

The very long-term prognosis and complications of lupus

nephritis and its treatment
L. BONO*, J . S. CAMERON and J . A. HI CKS
From the Renal Unit, UMDS Guys and St Thomas Hospitals, London, UK
Received 18 September 1998 and in revised form 5 February 1999
Summary
Although the short- and medium-term (510 years) and none of 67 patients actually followed more than
10 years subsequently went into renal failure. outcome of patients with lupus nephritis has been
studied extensively, there are very few data on the Induction treatment was with prednisolone, com-
bined with azathioprine in more severe forms of second and subsequent decades. We studied out-
come in 110 local patients investigated at a single nephritis, and from the middle 1970s to 1986, 30
with methylprednisolone and in 12 cases plasma centre before 1986, who all had potential follow-
up of more than 10 years (actual 231 years, median exchange. Seventeen other patients were treated
using oral cyclophosphamide during the 1960s. No 15.5 years). At last follow-up, 40 patients were dead
and 70 alive, nine of whom were on maintenance patient received i.v. cyclophosphamide as induction
therapy, although nine patients had this form of dialysis or transplanted, actuarial survivals being
84%, 72%, 62%, 61% and 54% at 5, 10, 15, 20 treatment later, largely because of non-compliance.
Serious complications of lupus and/or its treatment and 25 years for the group as a whole. Survival was
better in the cohort 197686 (n=60) than in that occurred in 49%: sepsis in 32, ischaemic heart
disease in 20, thrombosis in one and avascular nec- from 196375 (n=50) (90, 81 and 76% vs. 78, 56
and 43% at 5, 10 and 15 years, p<0.001). Sepsis rosis of bone in eight. In contrast, fracturing osteo-
porosis occurred in only three, and cataracts (12) and myocardial infarction (8) were the principal
causes of death. Of living patients with renal func- requiring surgery and diabetes mellitus in none. The
very long-term outlook of lupus nephritis, especially tion, 38% had normal urine and renal function, 11
were off all treatment (19%), 62% had persistent its more severe forms, has improved, but that with
current management strategies only a minority of proteinuria and 18% had reduced but generally
stable renal function. Renal failure, in those patients patients are able to stop treatment altogether, and
the incidence of serious complications is high. who developed it, occurred during the first decade
Introduction
Lupus is a disease with a peak incidence in adoles- suppressive treatment which has so dramatically
altered the outlook carries with it major toxicity. cence and young adulthood, affecting principally
young women.1,2 Until the past 30 years, the pro- Nevertheless, data are lacking on outcome of
young women with lupus nephritis who survive their gnosis for those with lupus nephritis as part of their
disease was very poor, but as prognosis has improved first decade. Only the papers of Moroni and col-
leagues,3 and Donadio et al.4 give information on under empirical treatment and more patients survive
long term, the later phases of the disease over outcome from 1020 years from onset. Thus we set
out to analyse retrospectively the outcome of our decades rather than years have become increasingly
important.2 This is especially so because the immuno- patients studied at Guys Hospital from 1963 to
Address correspondence to Professor J.S. Cameron, Elm Bank, Melmerby, Cumbria CA10 1HB.
e-mail: jstewart
-
cameron@email.msn.com
*Present address: Servizio Nefrologia e Dialisi, Ospedale G di Cristina, Piazza Montalto, 90134 Palermo, Italy
Association of Physicians 1999
L. Bono et al. 212
Table 2 Renal histology on initial biopsy 1986, who had a potential follow-up of 10 to
>30 years.
WHO class n %
I 0 0
Methods
II 22 21
III 27 25
Records were available on 243 patients with lupus
IV 43 37
nephritis who had been studied and followed at
V 18 17
Guys Hospital renal unit between 1963 and 1996.
VI 0 0
All patients had had a renal biopsy and all had at
Total 110
least four manifestations of lupus as described by
the American College of Rheumatology.5 Of these
243, 166 had their initial investigation in 1986 or
predominantly with proteinuria, the nephrotic syn-
earlier, and thus had 10 years or more of potential
drome being the commonest single renal presenta-
follow-up. Forty-three of these 166 patients were
tion. Two-thirds of patients had had other
excluded because they came from outside the UK,
manifestations of lupus diagnosed before their renal
and the reasons for referral and selection processes
disease became evident.
might differ from local patients; in addition, follow-
Approximately half of the patients showed dimin-
up was less complete in this group. Similarly, six
ished renal function as judged by estimation of
patients whose initial investigation as carried out
glomerular filtration rate using a single injection of
elsewhere within the UK and had tertiary or quatern-
51Cr edetate. About one quarter were hypertensive,
ary referral for various reasons to our unit, were
or had a requirement for hypertensive treatment.
excluded. This left 116 patients, in 110 of whom
adequate records were available to allow description
Renal histological findings at presentation
of their outcome and the complications they had
suffered. All 64 local patients of the 79 included in All patients had a renal biopsy (Table 2): two-thirds
of these showed aggressive patterns of lupus nephritis the paper published in this journal in 19799 were
included in the present study. (WHO classes III and IV) whilst one-fifth (21 patients)
showed a membranous pattern of glomerulopathy,
although the majority of these had some mesangial
deposits. Patients with mixed patterns of membran-
Results
ous and focal or diffuse proliferation were classified
as class III or IV, respectively.6 Presentation and initial treatment
Details of the 110 patients at the time of presentation
Induction treatment
and investigation are shown in Tables 13. Eighty-
The specific immunosuppression received by the
two were local Caucasians, 17 black African/Afro-
patients as induction therapy is shown in Table 3.
Caribbean, seven Indo-Asian and four Oriental.
The majority of patients with more severe histological
Ninety-seven patients (88%) were female and 13
appearances received prednisolone plus azathio-
(12%) male. Median age at presentation was 30.2
prine, although 17 patients in the 1960s and early
years (range 767 years). Presentation (Table 1) was
1970s had courses of oral cyclophosphamide lasting
from 3 months to 2 years in duration.7 No patient
Table 1 Clinical presentation of the renal disease
received intravenous bolus injections of cyclophos-
phamide for induction, although nine patients
n %
received this form of treatment later in their course
as part of maintenance therapy, all within the past
Nephrotic syndrome 49 45
510 years. In contrast, patients with milder forms
Persistent proteinuria 53 48
of histological lupus nephritis were in general treated
Acute renal failure 6 5
with prednisolone alone, or in a few cases no
Chronic renal failure 3 2
specific treatment to begin with.
Hypertensive* (>140/90) 23 25**
Reduced GFR (<80 ml/min/1.73 m2) 70 77***
Follow-up: treatment, outcome and Declining renal function 33 42****
complications
* Or requiring hypotensive therapy; ** based upon 93
One hundred and six of the 110 patients were
observations; *** based upon 91 observations; **** based
followed until 1996, or until death, for 231 years upon 77 serial observations of plasma creatinine concen-
trations. (median 15.5 years). Only four patients were lost to
Lupus nephritis: the very long term 213
Table 3 Initial immunosuppression received as induction therapy
WHO biopsy class II V III IV Total
No specific treatment 4 2 1 0 7
Prednisolone alone 8 5 6 3 22
Prednisolone+azathioprine 9 10 17 26 62
Prednisolone+oral cyclophosphamide 2 4 2 9 17
Prednisolone+i.v. cyclophosphamide 0 0 0 0 0
Prednisolone+chlorambucil 0 0 0 1 1
(not adequately recorded in 1 patient)
Thirty-two patients, all but three with class IV or severe class III appearances on biopsy were treated in addition with 13
courses of 1g boluses of intravenous methylprednisolone on three consecutive days during the period 1976 to 1986, and
14, all class IV, with plasma exchange daily for 7 days during the period 1978 to 1986.
follow-up, 218 years from initial investigation. However, in a univariant analysis no clinical para-
meters emerged as significant in this respect. Figure 2 Maintenance treatment consisted of oral predniso-
lone together with azathioprine in 70 patients and shows actuarial analyses of patient survival according
to a glomerular appearances on renal biopsy, and b oral cyclophosphamide in nine patients, all treated
between 1965 and 1970. Nine patients subsequently normal or reduced GFR at onset. In neither case
does the difference exceed a likelihood of 0.05 received 618 months treatment with intravenous
cyclophosphamide, using the protocol of the (Kaplan-Meier).
Figure 3 shows the timing of onset of renal failure National Institutes of Health,8 because of relapses
failing to respond to azathioprine and prednisolone in the study group. Despite the fact that in 67
patients actual follow-up exceeded 10 years, no or intravenous methylprednisolone with suspicion of
non-compliance. In general, treatment was continued further cases of renal failure were observed from
1025 years (although since this study was com- for a minimum of 5 years from onset before with-
drawal of treatment was considered, and in six pleted in 1996 the patient with the very late relapse
mentioned above required dialysis after 29 years patients, had to be re-started because of relapse
following deliberate or patient-motivated cessation follow-up).
of immunosuppression, in two patients as late as 22
Most recent status
and 25 years following presentation of renal disease.
A further patient taking 10 mg of prednisolone had
The most recent status of the 110 patients is shown
a severe biopsy-proven renal relapse 28 years after
in Table 4. Two-thirds of the patients were still alive
presentation followed by irreversible loss of renal
with renal function, their median age being by this
function. Because of this prolonged maintenance
time 46 years. Altogether, 18 patients developed
treatment, relapses were infrequent and no analysis
end-stage renal disease and received dialysis or
was done of outcome in relation to number of
transplantation, except one, in whom renal replace-
relapses.
ment treatment was withheld. The renal status of
those with surviving renal function in relation to
Survival
treatment is shown also in Table 4. Eleven patients
were well and off all treatment. The majority were Actuarial analyses of survival of patients form the
onset of renal disease are shown in Figure 1. Data still receiving immunosuppression, the majority in
the form of prednisolone, but some received predni- are shown also separated for the first decade and
the second decade of this study. There is a marked solone plus azathioprine in an attempt to permit
reduction in the dose of corticosteroids. improvement in survival in the 197686 cohort
compared with the 196375 cohort ( p<0.01, Forty patients had died, and the causes of death
(as far as they could be determined) are shown in Kaplan-Meier). For comparison the survival of a more
recent cohort, not included in this study, is shown Table 5. The main causes of death were sepsis and
cardiovascular disease; only three patients had who were investigated and treated between 1987 to
1996: survival was 83% at 10 years, similar to the developed malignancy, all lymphomas. Of 12
patients who died from causes other than vascular 197686 cohort. Thus during the past decade there
has been no further improvement in survival. disease and who had post mortems, eight showed
more or less severe coronary atheroma. In a number It was not the purpose of this study to analyse the
predictive value of features at onset, in view of our of cases the causes of death were either obscure or
multiple, and only the major cause of death is listed approach of varying therapy according to clinical
and histological severity of disease (Table 3). for each patient in Table 5.
L. Bono et al. 214
Figure 1. Actuarial survival estimates for the whole group (n=110) 196386; and two sub-cohorts, 196375 (n=50) and
197686 (n=60). Survival is better in the more recent cohort than in those seen before 1976 ( p<0.001, Kaplan-Meier
estimate). Data from a more recent cohort (198796, n=70) are included for comparison (open circles) and do not differ
from those seen during 197686.
are well known. It is a retrospective open case-note Complications of disease and treatment
study, gathered over a period during which manage-
The complications recorded are shown in Table 6.
ment changed, not only of the lupus but also of
No patient developed diabetes mellitus, although
hypertension, infections and other associated prob-
one patient had suffered type I diabetes before
lems. Data were not gathered in a systematic and
developing lupus. Systematic ophthalmoscopic
prospective fashion on likely complications.
examination was not carried out, although a number
Inevitably, the outcomes reported are to some extent
of patients were recorded as showing small posterior
a historical record, and do not represent the likely
cataracts. However no lens removal was needed in
outcome of patients presenting today, as our own
any patient in this cohort, although we are looking
more recent data show the apparent improvement
after one other patient biopsied abroad, who required
in survival noted in almost all series. However they
bilateral operations after 25 years corticosteroid
do indicate qualitatively, and to some extent quantit-
treatment. Likewise, although a number of women
atively, the type of problems faced in the long term
had DEXA bone density estimations after up to 20
by lupus patients.
years or more follow-up from onset under continuous
Certain features are surprising and some reassur-
corticotherapy, with results ranging from high normal
ing, for example the lack of induction of steroid-
to major thinning, only three patients had severe
related diabetes, in sharp contrast to findings over a
osteoporosis, in two leading to actual fractures.
similar period of time following transplantation. It
Cardiac echocardiography was not systematically
may be that the genotype associated with predisposi-
practised during this period, but only one patient
tion to lupus in some way protects against induction
required valve replacement for Libman-Sachs endo-
of diabetes. With better use of use of immunosuppres-
carditis, in association with a persistently high titre
sion, infections are likely to play a lesser role, at
of IgG anti-phospholipid antibody. Altogether 54
least in patients seen today, but the actual incidence
(49%) of patients suffered 68 major complications,
of infections (for example herpes zoster) does not
and 12 patients died as result of these.
seem to have diminished during the period of study,
despite improved survival.
Some of the common complications noted in our
Discussion
cohort of patients (thrombosis, infection, induction
of lymphoproliferative disorders, avascular necrosis The data presented here concern the largest series
of bone) are shared by the disease of lupus itself and of patients with lupus nephritis and follow-up of
its immunosuppressive treatment,1,2 and are unlikely more than a decade hitherto reported in detail.
Nevertheless, the deficiencies in this type of study to disappear. It is a sobering thought moreover that
Lupus nephritis: the very long term 215
Figure 2. a Actuarial survival estimates of patients with lupus nephritis according to histological class in the WHO
classification from renal biopsies obtained at onset. There is no significant difference between any of the curves (Kaplan-
Meier). b Actuarial survival estimates of patients with lupus nephritis and a glomerular filtration rate estimated by a single
injection of 51Cr-ethylene diamine tetracetate of greater or less than 80 ml/min/1.73 m2. There is no statistical difference
between any of the curves at a 0.05 level (Kaplan-Meier).
half the patients suffered one or more major com- anism that operates to promote thrombosis in patients
with lupus, and low plasma factor S concentrations plications, and this must be set against the improve-
ment in outcome discussed below. Most of the probably are of equal importance. In addition, the
many nephrotic patients will suffer from the pro- deaths resulted from complications in whole or in
part induced by treatment, particularly sepsis, and coagulant effects of hypoproteinaemia. We have
reported previously that 44% of our patients with not by the lupus per se, although it might be argued
that if the treatment is being applied appropriately lupus nephritis had anti-phospholipid antibodies,11
and more than half were nephrotic, so a high then death because of a complication of treatment
is a secondary effect of the disease. We have analysed incidence of thrombosis is not surprising. The patho-
genesis of the grossly increased incidence in coronary causes of death in lupus, including some of the
present patients, in more detail in a previous paper.10 artery disease compared with normal young or
middle-aged women (eight deaths from ischaemic The genesis of some of the complications found
in lupus such as thrombosis or vascular is multifactor- heart disease and eight other women with atheroma
at post mortem) is not clear, but apart from possible ial.2 Antiphospholipid antibodies are only one mech-
L. Bono et al. 216
Figure 3. Actuarially-calculated appearance of end-stage renal disease in the whole cohort of 110 patients. At 10 years,
67 patients were still in follow-up, having neither died nor entered renal failure. Nevertheless, no further patient entered
renal failure during the subsequent 15 years of the study up to 1996, by which time 16 patients were still being followed
(see text).
Table 4 Most recent status of patients with lupus after
Table 5 Causes of death in patients who died
very long-term follow-up
Principal cause n
Status n
Sepeis 10
Total 110
Septicaemia 4
Dead 40 (9 while
Pneumonia 3
on ESRD)
Meningitis 2
Alive 70
Varicella 1
Living patients
Ischaemic heart disease 8
On dialysis 4
Uncontrollable lupussepsis 5 (cerebral in 2)
Transplanted 5
Lymphoma 3 (1 post
With renal function 61
transplantation)
Gastrointestinal haemorrhage 2
Patients with renal function
Cerebrovascular accident 1
Normal 48
Murdered (already uraemic) 1
Reduced 11 (4 in CRF)
Not offered dialysis 1
Unknown 2
Uncertain 9
Normal urine 23
Total 40
Proteinuria 38
Treatment for proteinuria
None 11
Prednisolone 17
Table 6 Complications suffered
Pred.+azathioprine 28
Pred.+i.v. cyclophosphamide 3
Complication n
Unknown 3
Serious bacterial infection 18 (total sepsis 32)
Zoster/varicella 14
involvement of enhanced coagulation, interactions
Thrombosis 18
between hypercholesterolaemia and circulating
Neoplasm 6
immune complexes may contribute;11 a role for
Avascular necrosis of bone 6
corticosteroids remains controversial. Fracturing osteoporosis 3
Severe growth failure 2 As in the published literature on short-term out-
Severe myopathy 1 come of lupus nephritis,2 long-term outcome in our
Cataract requiring surgery 0
study improved during the period of study, and short-
Diabetes mellitus 0
term outcome in a subsequent cohort improved even
Total number of serious
further, both for survival and chronic renal failure.
complications 68 (14 per patient)
The latter event is now quite rare in lupus nephritis,
Total patients 54
affecting only about 15% of our patients even in the
Deaths resulting from
very long term. It is likely that current cohorts of
complications 12
patients may experience even less renal failure. In
Lupus nephritis: the very long term 217
our study, almost all cases of end-stage renal disease medium-term survival of the patients in both these
series using predominantly azathioprine as long-term emerged during the first decade, although we are
following a number of patients who have a reduced maintenance treatment is equally as good as that
reported using i.v. cyclophosphamide.2 It would be GFR and increased plasma creatinine concentrations
long after this point, and one patient required dialysis interesting to compare these data with similar figures
for patients treated with intermittent i.v. cyclophos- 29 years from onset after the present study had been
completed. However, many patients in moderate phamide for one or two years. However only nine
patients in the i.v. cyclophosphamide group of the renal insufficiency appear to have stable renal
function. NIH trials had been followed for more than 10 years,
and only one for 15 years;19 and so far no data have That these improvements are largely the result of
immunosuppressive treatment, first with prednisolone been reported on their very long-term outcome or
final treatment status. alone in the 1950s and 1960s, and then together
with cytotoxic agents in the 1970s and since, has
never been formally tested against a control group
receiving no specific treatment.12 Nevertheless it is
Acknowledgements
generally accepted that this is almost certainly the
We would like to thank the many colleagues who
case, and both a single-agent trial13 and meta-
helped in the care of these patients in the Adult and
analyses of controlled trials14,15 suggest that the
Paediatric Nephrology units, and the Histopathology
addition of a cytotoxic agent improves outcome over
department at Guys over the period of more than
prednisolone alone, although others dissent from this
30 years during which these data were collected.
view.16,17 Our data do not permit us to compare
Fred Compton gave valuable assistance with the
different immunosuppressive regimens usefully, and
actuarial analyses.
no study to date has demonstrated a superior effect
of one immunosuppressive regimen over another
(including intravenous bolus cyclophosphamide)
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