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Favorable outcome in diffuse proliferative glomerulonephritis of systemic lupus erythematosus.

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Favorable Outcome in Diffuse Proliferative
Glomerulonephritisof Systemic Lupus Erythematosus
Wallace V. Epstein and Henry Grausz
Life table analysis of 31 patients with biopsy proven diffuse proliferative
glomerulonephritis due to Systemic Lupus Erythematosus reveals a
77.7% five-year survival. Patients with similar lesions have, in the past,
had an approximate 20% five-year survival. The improved survival is attributed to the combined use of prednisone and chlorambucil and a panel
of frequently repeated laboratory tests that provides a guide to the activity of the systemic disease.
Although systemic lupus erythematosus
(SLE) involves multiple organ systems,
mortality rates during the first five years of
the disease are determined principally by
the nature of the renal lesion and factors
yet unknown which determine the rate of
evolution of the renal lesion (1-3). Overt
evidence of a glomerular lesion by light
microscopy of renal tissue obtained by
biopsy is to be expected in from 50y0 to
70% of cases (4). Entirely normal renal
tissue, by light and immunofluorescence
microscopy, from a patient with unquestionable SLE is rare (5).
The prognosis associated with the diffuse
proliferative glomerular lesion established
by light microscopy of renal biopsy mateFrom the Division of Rheumatic Diseases and
Nephrology. Department of Medicine, University
of California, San Francisco, California 94122.
Supported in part by grants 5-R01-AM01229 and
AM12753 from the National Institutes of Health,
Bethesda, Maryland, grant MSC521820-35032,School
of Medicine, San Francisco, and by grant 44491842075 from T h e Arthritis Foundation, Northern
California Chapter, San Francisco, California.
Presented at the annual meeting of the American Rheumatism Association Section of the Arthritis Foundation, Dallas, Texas, June 1972.
Address reprint requests to: Dr. Epstein.
Submitted for publication February 22, 1979; accepted August 14,1973.
rial has ranged from 20yo to 25% survival
after 5 years (2,6,7). In most studies this
survival is dated from the onset of multisystem disease rather than from the time
the patient first becomes the responsibility
of the managing group.
T h e present study concerns 67 patients
with SLE; 31 were found to have a diffuse
proliferative glomerulonephritis (DPG) on
first renal biopsy. A 5-year survival rate of
over 80% in this DPG group of patients
was observed in contrast to reported (1,2,6)
5-year survival rates of from 2174 to 25%
in patients with SLE who had the same
renal histopathologic lesion.
MATERIALS AND METHODS
Between 1966 and 1972 sixty-seven adult patients
(64 females, 3 males) were followed. All fulfilled
the tentative criteria for the diagnosis of systemic
lupus erythematosus as proposed by a Committee
of the American Rheumatism Association (8). These
patients were seen with sufficient regularity in the
Arthritis Clinic, University of California, San Francisco that we felt we were able to determine their
management both as inpatients and outpatients.
As is characteristic of most University Clinics, the
patient population presented a rather severe expression of the disease and most were receiving
therapy, usually adrenocorticosteriods, when first
seen.
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
129
EPSTEIN AND GRAUSZ
Table 1. Biopsy Classification and Survival of Total Patient Population
No. of Patients
Renal biopsy
Total
Deaths
Living
Diffuse
proliferative
31
25
Focal
13
10
3
2
3
2
18
15
67
55
Membranous
Normal (light)
Not done
Total
Percutaneous renal biopsy was performed in
49 of the 67 patients, permitting a precise histologic classification of the renal lesion. The reasons
a biopsy was not taken in 18 patients ranged from
failure to obtain written consent to the gravity of
their general illness when they were first seen.
Table 1 summarizes the total patient population,
the biopsy classification by light microscopy, and
the survival figures as of June 1972.
Except when stated, the remainder of this report
is limited to the 31 patients found to have DPG
by renal biopsy. Table 2 summarizes details of the
disease and drug therapy in these 31 patients.
Therapy
All patients were treated initially with prednisone in amounts sufficient to control the overt
clinical expression of their disease (usually 50 to
90 mg/day). T h e alkylating agent chlorambucil
was added to the medication program in 16 of the
31 patients with DPG because they were felt to
a) have progressive disease on the highest tolerable
dose of prednisone and/or b) the prednisone level
controlling the disease was itself producing unacceptable side effects. All patients received intermittent salicylate therapy for articular symptoms
and 20 received hydroxychloroquine, 200 to 400
mg/day, during periods of marked skin eruption.
T h e kinds and amounts of medications were determined by the clinical and laboratory criteria
to be described.
130
Primary Cause
Number
Renal
Marrow
Cardiac
Pulmonary embolus
Infection
Hemorrhage
Renal
Unknown
11
Laboratory Studies
Analysis of Renal Biopsy. All renal biopsy
material was classified using criteria outlined by
Baldwin et a1 (6). In particular all slides designated
as DPG showed mesangial proliferation and basement membrane thickening of all or nearly all
glomeruli observed. Three renal histologists classified each biopsy without knowledge of the patient’s
clinical course, laboratory test values, or the classification of the other histologists. There was agreement on all but four biopsies which were then
classified according to the majority opinion after a
repeat review. Further histologic information based
on immunofluorexent and electron microscopic
studies were not considered in assigning the classification of diffuse proliferative glomerulonephritis.
Organ System Function Tests. All patients had
complete blood counts, platelet counts, and urinalysis at least monthly. The serum creatinine, 24hour creatine clearance (Ccr), and quantitative
urine protein determinations were performed on an
average of every 6 to 8 weeks but at much closer
intervals during periods of exacerbation. Examination of the urine sediment was supplemented by
the quantitative 12-hour Addis count for formed
elements in urine. Function tests for other organ
systems were performed as indicated by the clinical
course.
Immunologic Tests. Serial determinations of LE
cell formation, antibody to double-stranded DNA
(ds-DNA) (9), total hemolytic complement, and
serum C3 content were performed serially. The
Arthritis and Rheumatism, Vol. 17, No. 2 (MarchAprli 1974)
32
14
120
60
37
84
26
14
10
21
180
36
38
60
32
60
84
26
59
117
180
36
28
36
60
27
84
36
60
28
48
SLE
Duration
Final
72
13.2
119
74
96
166
90
185
92
13
70
84
37
81
186
154
0.8t
0.8t
160
60
ND
70
25
1
75
6
9
15
22.0t
24
164
Initial
71
40
102
65
102
108
107
83
188
11
125
67
40
80
89
105
82
74
63
137
21
114
26
81
68
64
73
30
2
50
104
Ccr
1.2
3.0
3.4
0.6
4.0
1.8
13.0
1.4
1.2
12.4
ND
0.1
3.0
9.6
1.2
1.9
0.1
4.0
1.2
10.0
1+
3.2
11.4
2.1
1.o
4.5
4.6
0.6
4+
3.8
1.2
.
3.9
4.0
ND
ND
6.5
0.3
0.3
3+
4.8
4.4
I+
0.3
3+
0.31
0.09
1+
0.1
0.4
0.1
0.1
9.9
ND
ND
1.9
0.12
0.92
0.14
0.1
3.4
3+
6.0
Urine
Protein
W 2 4 hr)
Initial
Final
30/17
14/35
43/6.5
60/ 18
20/11
72/22
26/ 12.5
14124
9128
18130
160130
24145
34/8.5
55/17
30120
30150
66/42
24118
59124
105130
90125
30131
28/20
36/60
48/25
12/ 70
50/15
36/15
46/15
27128
46/ 10
44.4
34.5
12.2
15.6
36.2
38.3
37.1
22.5
19.6
ND
22.2
29.4
40.4
29.5
17.9
41.7
44.6
31.O
17.9
30.7
20.4
39.4
18.0
21 .o
43.8
11.4
21.1
54.0
14.1
52.8
27.8
14.3
29.6
14.8
19.5
13.3
5.0
31.4
8.8
11.6
ND
18.2
16.4
14.8
15.9
15.3
10.9
23.2
21.3
10.7
10.9
11.1
8.2
17.3
11.3
14.3
6.0
8.0
42.3
19.8
22.8
31.6
<20
320
20
<20
<20
40
<20
20
<20
ND
320
<20
20
<20
<20
<20
<20
<20
<20
80
80
20
320
640
40
640
160
40
80
320
40
640
320
320
80
320
320
40
160
160
1280
1280
160
320
160
320
80
1280
320
1280
640
320
160
640
160
320
1280
320
20
160
640
20
Prednisone
Duration1rn
(rno)/rngld
CHm
(u/rnl)
Initial
Final
Urine
L-chain
(ag/ml)
Initial
Final
0
O*
Ott
814H
1316f-f
ott
514.2tt
Ott
1215
O$
1014.5
0
0
2714.2
1417.0
0
0
0
0
0
517.2
1412.5
24/6.0
17/40
2215.5
0
35/35
29/3.5§
0
14/4
4/41
Chlorarnbucil
Durationlrn
(mo)lmg/d
‘rn (mean), mg/d (milligrams per day); +Serum creatinine (rng/rnl); ttDied as of June 1972; Clinical Change after June 1972, $Alive on
hemodialysis; §Alive on hemodialysis; [[Diedon hernodialysis; **Died-infection CCr 44
16F
14F
26F
18F
27F
25F
19F
18F
28F
23F
17M
30F
20F
19F
20F
29F
23F
21 F
14F
18F
18F
20F
45F
38F
34F
20F
21F
21 M
17F
24F
36F
AgelSex
onset
Total (mo)
Table 2. Systemk Lupus Erythematoour with Diffuse Proliferative Glomarulonephritiron Renal Biopsy as of June 1972
EPSTEIN AND GRAUSZ
Table 3. Diffuse Proliferative Lupus Nephritis:
Features at Onset
seen or during a period of less than three
months prior to coming under our care
with the series of Baldwin et a1 (6) anaPresent Study
Baldwin era/
lyzed
for these criteria at time of onset of
Total
Total
disease.
Feature
Patients Number Patients Number
As was true in the Baldwin series all
Active systemic
patients evidenced active SLE in more than
lupus erytwo organ systems during the initial phase
31
24
24
thematosus 31
of
their disease and hematuria, proteinuria,
Hematuria
30
27
20
13
Proteinuria
30
26
24
24
and a nephrotic syndrome as part of the
Nephrotic
initial presentation were present to about
30
15
24
14
syndrome
the same extent in both groups of patients.
Azotemia
31
13
23
13
T
h e most marked difference could be
CHm (25-42)
found
in the number of patients with azoNormal
30
4
30
3
20-25
temia at onset or during the first three
15-20
30
7
months of overt disease activity; 41.0y0 in
12-1 5
30
6
the present and 56.5% in the series of
-42
30
10
Baldwin et al (6). In the present study a
24-hour corrected creatinine clearance beserum content of protein complexes or IgC; capable low 70 ml/min was taken as evidence of
of precipitin line formation with C l q in an aga- diminished renal function, while in the
rose medium was determined at variable intervals Baldwin series a BUN over 35 mgyo placed
in each patient (10-12).
the patient in the azotemic group. Since a
Urine L-chain Concentration. An effort was
general
correlation has been found bemade to determine the urine free L-chain protein
tween
diminished
serum total hemolytic
concentration at least twice monthly throughout
complement
and
active
renal disease (15,
the period of observation. The urine concentration
was determined by a precipitin reaction using
16) it was of interest to find that only 4 of
doubling dilutions of an afternoon urine specimen 30 patients tested at or near the onset of
and a rabbit antiserum specific for the normally
their disease had a normal total hemolytic
obstructed L-chain sites of IgG as described previcomplement.
ously (13J4).
RESULTS
Since no treatment control group is included in this study, we have attempted to
establish whether the 31 patients with biopsy proven diffuse proliferative glomerulonephritis could be compared with patients with SLE assigned a similar renal
lesion by other groups. T h e 24 SLE patients with a diagnosis of DPG by renal
biopsy reported by Baldwin and co-workers
(6) have served as our historic control.
Table 3 compares clinical characteristics of
the present group of patients when first
132
Renal Biopsy
T h e designation of these patients as having DPG was based entirely upon renal
biopsy evidence. I n all but three, initial
examination of the urine sediment showed
increased numbers of red blood cells together with hyaline, granular and occasionally red blood cell casts.
T h e light microscopic criteria for a diagnosis of DPG were those described in the
Baldwin et a1 study (6) and representative
glomeruli of six of the 31 patients are
shown in Figure 1A-F. As stated in the
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
Photomicrographs of six renal biopsies selected at random from the 31 biopsies classified as diffuse proliferative glomerulonephritis. Diagnostic areas of biopsies are shown.
Fig 1A (Case 20). Low power shows diffuse proliferation of two of three glomeruli shown (X100).
High power shows diffuse proliferation involving the whole glomerulus (X250). B (Case 1). Low power
(X40) shows 3 diffusely proliferative glomeruli with marked intersitial infiltration. High power (X250)
shows diffusely proliferative glomerulus with crescent formations. C (Case 16). Low power (X40) shows
5 diffusely proliferative glomeruli with interstitial infiltration. High power (X250) shows diffuse proliferation with crescent formation. D (Case 5). Low power (X100) shows 3 diffusely proliferative glomeruli with marked interstitial infiltration. High power (X250) shows diffuse proliferation with crescent formation. E (Case 17). Low power (X40) shows five diffusely proliferative glomeruli. High
power (X250) shows interstitial proliferation with crescent formation. F (Case 22). Low power (X40)
shows 3 diffusely proliferative glomeruli. High power (X250) shows diffusely proliferative glomerulus
with crescent formation.
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
133
EPSTEIN AND GRAUSZ
Materials and Methods section, three renal
histologists independently agreed on the
diagnosis in all but four biopsies and a
majority of the observers decided the diagnosis in these four. Mesangial proliferation
was present to some degree in all glomeruli
observed and basement membrane thickening or staining abnormality was uniformly
134
present. N o effort was made to delineate
the DPG group further as has been attempted by Hayslett et a1 (17). Clear differences do exist in the intensity of the inflammatory prccess in different biopsies all
classified as DPG, but no completely satisfactory subclassification could be agreed
upon. Although not included as part of the
Arthritis and Rheumatism, Vol. 17, Nu. 2 (MarchApril 1974)
DIFFUSE PROLIFERATIVE GLOMERULONEPHRITIS
FIRST
-
CURRENT
DETERMINATION
DETERMINATION
...............
NORMAL
Ccr
> 70
Ccr
< 70
Fig 2. Urine free light chain protein concentrations at start and end of period of management. The
upper group all had Ccr values over 70 ml/min at the conclusion of the study, those below ended
with values below 70 ml/min.
classification criteria, virus-like inclusion
bodies were observed in electron micrographs of each of the patients irom whom
tissue was submitted for electron microsCOPY (18).
Table 2 summarizes the initial and final
creatinine clearance (Ccr), degree of proteix:uria, CH,, level and urine Lc levels.
As has been reported by others, urinalysis
furnishes an inadequate guide to the extent of renal involvement in the glomeru-
lonephritis of SLE (19). Patient 25 died
due to infection secondary to pancytopenia
associated with chlorambucil therapy. Death
in Patient 27, who had been followed for
6 years, was associated with a diminished
renal excretory ability compared to the initial value but actually the patient had a
normal Ccr through the 6 years of care and
developed intractable myocarditis with prerenal azotemia and diminished renal function terminally. Urine sodium concentra-.
Arthritis and Rheumathm, Vd. 17, No. 2 (March-April 1974)
135
EPSTEIN AND GRAUSZ
tion of 2 mEq/liter in the terminal phase
of this patient’s illness indicated good renal tubular function (29). Patient 23, who
received chronic hemodialysis and is the
subject of a separate report (21), died from
pulmonary infection 10 months after this
study was completed.
Serial determination of the urine concentration of free L-chain protein has
proven a valuable guide to disease management (Figure 2). All 31 patients had
urine L-chain concentrations of 20 pg/ml
or higher initially. Throughout their
courses, exacerbations of SLE were associated with or preceded by rising levels of
urine free L-chain protein and successful
treatment was associated with decreasing
values, although not always to values less
than 20 pg/ml. Clinical exacerbations did
not always involve overt exacerbation of
the renal disease as reflected by increased
proteinuria, cellular elements or decreasing creatinine clearance. As shown in Figure 2, of 20 patients with current Ccr values over 70 ml/min twelve have less than
20 pg of free L-chain per milliliter of urine.
In the course of a clinical exacerbation the
urine L-chain concentration may vary between 20 to 1280 pg/ml with no significant
change in Ccr. Serial determination of the
serum total hemolytic complement, serum
C3, and the concentration of serum antibody to double stranded DNA conform to
observations of others (22) relating change
in these determinants to exacerbation and
remission of SLE.
Figure 3 provides an illustration of the
ability of measurements such as urine Lchain protein, total serum complement,
and antidouble-stranded DNA taken together to anticipate the clinical onset of
an SLE exacerbation. In no instance have
we observed either continuation or progression of SLE nephritis as long as the
urine L-chain concentration remains in the
136
normal range of less than 20 pg/ml of
unconcentrated urine.
Survival Analysis
A life table analysis for survival of the
31 patients with DPG of this study (as of
June 1972) and the 24 patients of the
Baldwin et a1 (6) study was performed.
Using the years since onset of multisystem
disease, a 77.7% five-year survival was
found based on deaths due to all causes up
to June 1972. Updating these results to
June 1973 (2 additional deaths-see Table
2) gives a five-year survival of 73.5%. The
P value ( t test) (P<0.005) shows that these
values differ significantly compared to the
five-year survival of the 24 patients with
DPG studied by Baldwin and co-workers
(23%). Similar analysis limited to the period since these patients came under our
care shows an equally significant difference
when compared to the Baldwin series. This
comparison was with the extent of “years
since onset” as recorded in the experience
of Baldwin et a1 (6).
Management
Table 2 details the drug management of
each patient together with vital statistics
and essential organ dysfunctions.
The management of these 31 patients
may be divided into that used during periods of disease activity and that used during periods of remission. Comments are
limited to the use of prednisone and chlorambucil, although the intermittent use of
hydroxychloroquine usually for SLE skin
lesions and of aspirin for arthalgia may
have contributed to the results.
As shown in Figure 3 and as has been
reported elsewhere (15,16,21,22) we have
found that currently available immunologic laboratory tests provide a guide to
drug management in the initial episode.
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
DIFFUSE PROLIFERATIVEGLOMERULONEPHRITIS
72r
CREATNNE
CLEARANCE
rnl/rnin
URINARY
PROTEIN
9/240
I
10
o E l l l l l ~ " lI
I
I
I
I
I
I
II1111
I
I l l
*
I
I
PREDNISONE
w/dv
-L
CHLORAMBUCIL
mg/doy
8
4
0
uulllllllllllul
I
DECIJ
1
1
1
1
1
1
F M A M J
1967
1
J
1
I
A
1
1
s o
1
I
1
N D
C
IJAN
T
1968
'
x
Fig 3. A 23-year-old white female first seen in September, 1966 with acute glomerulonephritis,
positive LE cell preparation and with the laboratory findings shown above. Renal biopsy revealed
diffuse proliferative glomerulonephritis and she was treated with prednisone, 60 mg/day. Over the
next 2 weeks she exhibited rising diastolic blood pressure levels, convulsive episode, and no improvement in organ function or laboratory test abnormalities. Chlorambucil was added to prednisone
therapy as shown, and over the next 3 months there was a definite improvement in urine sediment
abnormalities, proteinuria as well as creatinine clearance, and serum complement levels. Because of
extreme side effects due to prednisone the agent was tapered and stopped during April 1967. At
that time all organ system abnormalities had reversed; creatinine clearance was over 100 ml/min
proteinuria was less than lg/day and both serum and urine L-chain protein were less than 20 ,,g/
ml. Chlorambucil was discontinued in August 1967 and at this time the only new evidence of disease
activity was the reappearance of detectible urine L-chain proteins. During October and November
rising levels of urine and serum L-chain protein together with rising levels of serum antibody to dsDNA and decreasing CHm levels were observed together with an increase in both red and white
cells in the urine sediment. By December a full exacerbation of polyarthritis and glomerulonephritis
was accompanied by a pyosalpinx which prevented administration of either chlorambucil or prednisone but finally in January 1968 both agents were restarted with clinical as well as laboratory
parameters improved. By April 1968 creatinine clearance was somewhat diminished. Both prednisone
and chlorarnbucil were withdrawn during April 1968, and by March 1969 she remained well except
for increased cells in the urine sediment and moderate anemia. Serum creatinine at that time was
1.0 mg/ml and creatinine clearance, 70 ml/min.
during exacerbations, and during periods
when the patients feel well and usual tests
of organ system function suggest disease
remission.
All 31 patients in this group with DPG
received prednisone in the treatment of
the first observed clinical attack. Daily
amounts varied from 20 to 300 mg per day.
The highest dose being used in the treatment of one patient with extensive central
nervous system involvement.
After 6 weeks of prednisone therapy the
patient is evaluated for the degree of response and the extent of steroid side ef-
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
137
EPSTEIN AND GRAUSZ
fect. Continued hypocomplementemia (<20
CH,, units/ml), continued L-chain proteinuria (>80 pg/ml) and continued elevation of serum antibody concentration to
ds-DNA (>200 cpm) all indicated a n inadequate response to prednisone. No instance of continued clinical activity after
normalization of these three measurements
was encountered. I n the sixteen instances
in which chlorambucil was added to prednisone at least two of these three laboratory determinations remained abnormal together with continued evidence of organ
system inflammation. Similarly, the reappearance of elevated antibody levels to dsDNA, elevated urine L-chain or hypocomplementemia when prednisone was reduced
below 50 to 60 mg/day whether or not
there was other evidence of disease activity
constituted adequate reason to add chlorambucil. I n 3 cases it was the magnitude
of the Cushingoid side effects at the minimum amount of prednisone intake required to control clinical and laboratory
manifestations that led to addition of
chlorambucil. In these three instances it
was possible to further reduce the daily
prednisone intake after a chlorambucil effect was apparent. Chlorambucil was started at 2 mg/day and followed by weekly
complete blood counts, including platelet
counts. At about 2-week intervals the daily
dosage of chlorambucil was raised by 2 mg
until either: a) there was a distinct improvement in both clinical and laboratory
expressions of disease activity; b) the white
blood count fell below 4500 and/or the
platelet count below 95,000; or c) the daily
dosage reached 10 mg/day (adult dose).
After a clinical response the daily dose
of prednisone was reduced gradually and
where possible was withdrawn entirely.
This has been possible for variable periods
in 8 of the 15 patients receiving both prednisone and chlorambucil. I n most instances
138
the patient could be maintained on less
than 10 mg of prednisone per day. After a
drug-induced remission persisted for 2 to 3
months, chlorambucil was reduced by approximately 2 mg/day each month.
I n 17 of the 31 patients there were intervals, usually several months in duration,
when both prednisone and chlorambucil
were withdrawn entirely and all tests remained normal except for urine L-chain
values of 20 to 40 pg/ml.
Interval Management
Perhaps the central aspect of the management program has been the bimonthly
measurements of urine L-chain protein
and monthly determination of total serum
complement and antibody to ds-DNA. A
pattern of rising urine L-chain has presaged a clinical exacerbation even when
the major organ system undergoing disease
exacerbation was other than the kidneys.
In the case illustrated and described in
Figure 3, managed during 1967-1968, medication today would have been restarted
during September or October 1967 when
rising urine L-chain concentrations and
serum anti-DNA levels suggested the exacerbation of December could be anticipated.
Despite the patient's unchanged urinalysis and sense of well-being we restart or
raise the level of prednisone when two or
more of the following change: a) urine
L-chain concentration to over 80 pg/ml,
b) decrease in serum complement to less
than 15 CH,, units/ml, c) increase in antiDNA to over 200 CPM. Patients in whom
unique immunologic abnorm.*ities such as
circulating complexes reactive with Clq
(1 1) or antibody to a serum thermolabile
substance (12) appear during disease activity will be restarted on treatment when
these substances reappear during periods
of apparent disease remission. I n most
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
DIFFUSE PROLIFERATIVE GLOYERULONEPHRITIS
cases the pattern of laboratory abnormal- vival for 10 such patients, indicating that
ities can be reversed with little or no this finding on renal biopsy denotes the
awareness on the part of the patient that poorest prognosis for survival. The present
analysis devoid of treatment controls, was
an exacerbation was in progress.
undertaken in the belief that it might be
possible to compare the experience of different groups when treating biopsy proven
Complications of Chlorambucil Therapy
Sixteen patients received chlorambucil diffuse proliferative glomerulonephritis.
for an average of 16.6 months with the
Because the experience presented by
longest continuous period of administra- Baldwin et a1 (6) was in keeping with that
tion being 36 months at an average daily of several other studies (2,4) and because
dosage of 4.7 mg. Five episodes of marrow we could rather directly match our 31 cases
depression sufficiently serious to require with their 24 cases of DPG we used their
withdrawal of chlorambucil were observed. experience as our historic control.
In 1 patient marrow depression proved to
We have shown that our patients were
be irreversible and that patient had re- not dissimilar to those of the Baldwin
ceived the drug for 5 months at an average series by evidence of multisystem involvedose of 4.2 mg/day. Three patients have ment, manifestations of the renal disease
had four mild-to-moderate episodes of her- process and the characteristic hypocomplepes zoster skin infection while receiving mentemia occurring in the active phase of
both prednisone and chlorambucil.
the disease (16). T h e determination of renal excretory ability by creatinine clearance is, we feel, more meaningful than the
DISCUSSION
BUN determination used in the Baldwin
T h e pattern of diffuse proliferative study particularly when prednisone therglomerulonephritis as an inexorably pro- apy is being used (6). We have endeavored
gressive glomerular lesion in patients with to use the same criteria for histologic clasSLE has been commented upon by multi- sification as used by Baldwin and although
ple authors since the early reports by Pol- some differences of gradation within the
lack and co-workers in 1964 (1). In the DPG group can be delineated, we believe
analysis by Estes and Christian at Presby- that none of the 31 patients of this study
terian Hospital of Columbia University (2), had the so-called focal lesion with its imthe estimated 5-year survival for all pa- plied favorable prognosis. The incidence
tients with SLE had improved from 50% of focal and DPG lesions among the 49
in 1954 (Johns Hopkins experience) to patients biopsied is the same as that re70% in 1969 (Columbia Presbyterian ex- ported by others further indicating a repperience). It has been in the subgroup resentative population by both clinical and
designated active glomerulonephritis or biopsy criteria (1,6).
The efficacy of immunosuppressive therdiffuse proliferative glomerulonephritis
that a continued very poor prognosis has apy almost invariably accompanied by
remained. Pollack et al in 1969 (7) found adrenocorticosteroid therapy in lupus nea 21% five-year survival for 47 patients, phritis has recently been reviewed by
Baldwin et al (6) a 23% five-year survival Skinner and Schwartz (23). These authors
in 1970 for 24 such patients, and Estes and stress the difficulty in evaluating the theraChristian (2) in 1971 a 25% five-year sur- peutic efficacy of such agents in a disease
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
139
EPSTEIN AND GRAUSZ
of such a variable natural history. A controlled double blind trial of cyclophosphamide therapy for 10 weeks in 13 patients
with lupus nephritis (24) makes clear that
such agents can unquestionably produce
serologic improvement; however manifestations of proteinuria, urine sediment abnormalities, and creatinine clearance were
not substantially different in the treatment
and the control group. Administration of
the alkylating agent chlorambucil is associated with the danger of depression of
bone marrow elements. Weekly blood
counts must be performed assiduously. Gastrointestinal, bladder, and hair loss problems so commonly found with the use of
cyclophosphamide (24) are not found.
Herpes zoster infections were noted but
could not clearly be associated with chlorambucil. As noted by Skinner and Schwartz
(23) only two studies of combined corticosteroid and immunosuppressive therapy in
groups of over 10 patients has been reported. I n one (25), 3 of the 11 patients
were said to have improved when azathioprine was added to prednisone, and in the
other (26) it was not certain that clinical
improvement accompanied what seemed to
be serologic improvement. Hayslett et al
(17) have recently reported clinical and renal biopsy improvement in 10 of 16 patients treated with prednisone and azathioprine.
There would appear to be two major
reasons for the improved 5-year survival
of the present study. First we have added
an immunosuppressive agent to the therapeutic program of these patients as soon
as it was clear that a sustained dose level
of prednisone causing serious steroid side
effects would be required to control clinical and laboratory manifestations of the
disease and second we have withdrawn
medication and then restarted medication
based more on special laboratory tests than
140
on direct tests of organ system insufficiency
or inflammation-eg, proteinuria or urine
sediment abnormality. I n particular the
urine concentration of L-chain protein, a
substance metabolized by enzymatic proteolysis after glomerular filtration (27,28) has
proven especially useful. Elevated urine
concentrations of L-chain protein regularly
return to the 20 to 40 pg/ml level after
serum complement (CH,,, and C3), antibody to DNA and complexes that precipitate with Clq in agarose have returned to
normal. T h e rate at which administered
medication can be reduced can be guided
by such measurements. Since we have not
observed an exacerbation of the renal disease with a sustained normal urine L-chain
concentration it seems probable that the
renal tubular lesion is an early manifestation of the process and anticipates or
occurs concomitan tly with the glomerular
lesion. T h e role of over production of Lchain in L-chain proteinuria of SLE has
not been fully evaluated.
Other factors which must be considered
in what appears to be a favorable outcome
in these patients include improved agents
to manage intercurrent infection and the
possibility that despite the appearance of
the renal biopsy we were dealing with a
subset of DPG that has a naturally benign
5-year prognosis.
T h e detection of rising urine L-chain
levels during clinical remission especially
if associated with changing values for complement and anti DNA has resulted in
more closely spaced Clinic visits, examination of urine sediment and this may result
in earlier recognition of disease reactivation warranting restarting medication. T h e
failure of urinalysis to reliably indicate
SLE activity has been stressed by others
(19). Once the manner of clinical exacerbation for a given patient becomes known
we are more willing to treat changing lab-
Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
DIFFUSE PROLIFERATIVE GLOMERULONEPHRITIS
oratory tests per se. Caperton et a1 (29) in
their report of a favorable experience in
treating a group of 126 patients with SLE
similarly stress frequent (1 to 3 month)
reexamination of patients in what appear
to be disease remission. Using serum complement and anti DNA antibody levels
they too reinstitute therapy based on worsening clinical or chemical parameters. The
fact that their favorable experience was
achieved using prednisone and azathioprine stresses the fact that it is probably
the time of institution of therapy rather
than the use of a particular agent that
favorably influences the prognosis. Snaith
et a1 (30) treated 6 patients with SLE with
chlorambucil and the results were favorable, although only 1 had a severe lesion,
demonstrated by renal biopsy and a previously unfavorable course on prednisone
alone. The time of administration of cytotoxic drugs as a factor in antibody synthesis, delayed hypersensitivity, and allergic tissue injury seems quite critical. The
efficacy of a properly timed single dose of
cyclophosphamide administered to NZB/NZW mice has emphasized the importance
of timing. Whether the action is by immunosuppression, by antiinflammatory activity. or by both is not certain (31).
If a pattern of laboratory tests can be
evolved which definitely reflects the underlying disease process and anticipates disease
exacerbation it should be possible to use
the least amounts of medication to treat
disease and to prevent its exacerbation. We
suspect that a far wider group of tests will
be required than presented here to cover
all SLE disease variants. T h e survival statistics presented indicate that early and
aggressive use of prednisone and, when
needed, chlorambucil can significantly improve the 5-year survival of patients with
SLE and diffuse proliferative glomerulonephritis.
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