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Mortality in lupus nephritis.

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764
MORTALITY IN LUPUS NEPHRITIS
JACOB KARSH, JOHN H. KLIPPEL, JAMES E. BALOW, and JOHN L. DECKER
The principal causes of death-of 68 patients with
lupus glomenrlonephritis were reviewed. Renal failure
(m),
vascular events (25%), and infections (16%)were
the predominant causes. Dfluse proliferative glomerulonephritis was associated with an increased frequency of
renal failure. A bimodal pattern of early deaths due to
active lupus and sepsis and late deaths from vascular
events was found superimposed on a constant rate of
death from renal failure.
Prior to the availability of corticosteroids, a frequent event occurring early in the course of systemic
lupus erythematosus (SLE) was death (1). The introduction of corticosteroids in the early 1950s provided
effective therapy for the acute fulminating form of the
disease and resulted in improved survival. More recently the use of antibiotic and antihypertensive therapies and intensive care facilities has enhanced the ability to manage many of the complications of SLE and
further prolonged survival (24).
Death, however, still occurs with unfortunate
frequency. The importance of renal involvement as a
major cause of both morbidity and mortality is well established (1-8). Current concepts suggest that the progression and eventual outcome of renal disease are inFrom the Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland.
Jacob Karsh, MD: Fellow of the Canadian Arthritis Society;
John H. Klippel, MD, James E. Balow, MD; John L. Decker, MD:
Clinical Director, NIAMDD, NIH.
Address reprint requests to Dr. Jacob Karsh, Building 10,
Room 9N218, National Institutes of Health, Bethesda, Maryland
20014.
Submitted for publication September 25, 1978; accepted in
revised form February 6, 1979.
Arthritis and Rheumatism, Vol. 22, No.7 (July 1979)
fluenced by the type of glomerular pathology (9), the
persistence of serologic abnormalities (lo), and corticosteroid (2) or cytotoxic (1 1) therapies.
A new and ominous trend in the mortality of
SLE patients is the increasing incidence of cardiovascular diseases as late causes of death. Myocardial infarctions and advanced arteriosclerotic heart disease,
particularly in young SLE patients, have become increasingly prevalent causes of mortality in the steroid
era (3,4,7,12,13).
The Arthritis and Rheumatism Branch of the
NIH has a long and ongoing interest in the evaluation
and management of patients with lupus nephritis. This
report retrospectively analyzes the causes of death of 68
patients with lupus nephritis treated since the advent of
corticosteroid and immunosuppressive therapies. Our
findings show that renal failure, infectiohs, and cardiovascular events are the leading causes of death in patients with lupus renal disease.
PATIENTS AND METHODS
During the period 1954 to 1977, a total of 428 patients
with SLE (14) were referred to the NIH Clinical Center for
participation in research protocols evaluating lupus nephritis.
The criteria established for inclusion in the present report included evidence of nephritis as determined by proteinuria, an
abnormal urine sediment or impaired renal function, and a
d e h e d mode and date of mortality. As of January 1978, there
have been 94 deaths in our patient population; 5 in patients
without evidence of renal disease and 21 in patients in whom
detailed information concerning the cause of death is unavailable. Thus, 68 patients satisfy the study criteria and form the
basis of the report.
The primary causes of death were ascertained from reviews of NIH medical records alone in 9, from NIH records
and postmortem examinations in 36, from postmortem exami-
MORTALITY IN LUPUS NEPHRITIS
nations performed elsewhere in 1 I, from direct correspondence with physicians attending the patients at time of death
in 10. and from police reports in 2 (an automobile accident
and a suicide). Renal failure was specified as the primary
cause of death in all cases manifesting terminal creatinines in
excess of 8 mg/dl despite terminal complications such as infection, congestive heart failure, or intracranial bleeding. Five
patients currently alive and maintained on chronic hemodialysis were excluded from the analysis. When the terminal
creatinine was less than 8 mg/dl, the primary cause of death
was assigned to the clinical event contributing most to the patient’s demise, with the recognition that other causes may
have significantly contributed to the terminal event. Neurologic events were divided into those occurring in the chronic
clinical setting of active CNS lupus and those occurring
acutely with relatively stable, inactive SLE.
Deaths occurring in the first 2 years after the onset of
renal disease are referred to as early deaths whereas those occurring after 2 years are designated late deaths.
RESULTS
The primary causes of death of the 68 SLE patients with renal disease and the survival from the onset
of renal disease are indicated in Table 1. Renal failure
was the single most common cause of death (40%) and
accounted for at least 20% of the deaths during each 2year interval after the onset of renal disease. Three patients survived more than 8 years before succumbing to
renal failure; 2 of the 3 had received chronic hemodialysis, including the longest survivor (168 months).
One survivor of 93 months received a cadaver kidney
transplant but died of complications within 1 month after the procedure.
Eleven deaths (16%) were ascribed primarily to
765
infections. Infectious deaths occurred most frequently
early with a short median survival of 13 months from
the onset of renal disease (Table 2). Gram negative and
gram positive infections were seen with equal frequency. Both cases of Pneumocystis carinii pneumonia
developed in patients receiving cyclophosphamide and
occurred in the setting of mixed pulmonary infection
with other significant pathogens. The Staphylococcus
aureus bacterial endocarditis developed on a mitral
valve scarred by Libman-Sachs vegetations.
Eight patients dying from renal failure, central
nervous system (CNS) lupus, or pulmonary embolism
had terminal courses complicated by serious infections
(Table 3). Gram negative organisms predominated in
this group. The combination of terminal infections
listed in Tables 3 and 4 thus includes 19 major infectious events at the time of death of 28% of the mortalities.
The combination of all cardiovascular events, including pulmonary embolism, sudden death, and hypertensive cerebrovascular accidents (CVA) accounted for
17 deaths (25%). These deaths constituted 14% of the
early and 33% of the late deaths. The median survival of
26 months for CVA patients was relatively short but
that for pulmonary embolism and sudden death was
prolonged to 6 1 and 86 months, respectively.
All 5 patients dying from a hypertensive CVA
had severe long-standing uncontrolled hypertension
and developed an acute deterioration of central nervous
system function in the setting of otherwise clinically
stable SLE. Autopsies were performed on 3 patients
with the findings of fibrinoid necrosis of arterioles and
Table 1. Cause of death in 68 patients with SLE nephritis
From onset of renal disease
Primary cause of death
No./%
Age at death
(years),
mean SD
Renal failure
Infection
Vascular events
Pulmonary embolism
Sudden death
Hypertensive cerebrovascular accident
Active lupus
Cardiorespiratory failure
Hepatic failure
CNS lupus
Miscellaneous*
21/40
11/16
32f2
33f5
35
13
10
8
17
3
33f4
44f3
30 f 5
61
86
2
26
2
4
6
3
2
5/7
24 f 7
23
25 f 8
30 f 3
19
3
56
30
5
I
0
1
0
2
4
TOTAL
68/100
32f I
31
29
39
Patients
*Gastrointestinal hemorrhage 2; malignancy I; trauma 2.
*
Median
survival
(months)
Number dead in
5 2 years
>2 years
17/25
6
6
5
8/12
5
1
0
0
KARSH ET AL
766
Table 2. Infection as the primary cause of death in lupus nephritis
Year of
death
Survival from
onset of
renal disease
(months)
Terminal
creatinine
mg/dl
Cytotoxic drugs
received
9
1.o
1.1
2.5
I .o
No
No
Chlorambucil
Cyclophosphamide
1969
1970
44
9
1.o
2.5
Cyclophosphamide
Cyclophosphamide
1970
1973
1975
I976
1977
20
64
2.5
3.4
I .o
I .o
2.5
Azathioprine
Azathioprine
Azathioprine
Cyclophosphamide
No
1954
1963
1969
1969
1
2
1
21
48
13
evidence of both old and new areas of cortical hemorrhage and infarctions. There was no evidence of active
arteritis of either the cerebral or renal vessels.
Assessment of the 6 cases of sudden death
showed that all patients had preexisting cardiovascular
disease as manifested by hypertension, coronary artery
disease, or valvular abnormalities (Table 4). A1 patients
had been treated for prolonged periods with corticosteroids. All but one patient died suddenly outside the hospital and all deaths occurred after at least 2 years of
renal disease. Postmortem examinations revealed acute
myocardial infarctions in the presence of severe, advanced atherosclerotic coronary artery disease in 2 patients and an acute fibrinous pericarditis, evidence of an
old myocardial infarction, and Libman-Sachs endocardial vegetations on the mitral valve in the third case.
Active SLE despite corticosteroid therapy accounted for 6 early deaths and included cardiorespiratory failure in 5 patients and one case of rapidly progressive hepatic failure. Available postmortem
Organisms
Staphylococcus aureus
Pseudomonas aeruginosa
Escherichia coli
Pneumocystis carinii,
Cryptococcus neoformans,
Mycobacterium tuberculosis,
C ytomegalovirus
Pseudomonas aeruginosa
Pneumocystis carinii, Staphylococcus
aureus
Mixed flora
/3-hemolytic streptococcus
Staphylococcus aureus
Diplococcuspneumonia
Mixed flora
Involvement
Bacteremia
Bacteremia
Bacteremia
Pneumonia
Bacteremia
Pneumonia
Pneumonia
Bacteremia/abscess
Mitral valve
Epiglottitis
Paratracheal abscess
examination of these patients demonstrated nonspecific
acute and chronic inflammation of affected organs.
Central nervous system (CNS) lupus, as conventionally
understood, was responsible for 2 late deaths. The CNS
manifestations in one patient consisted of terminal refractory grand ma1 seizures and a chronic severe psychosis in the other patient. In both cases the gross and
microscopic examinations of the brains showed entirely
normal results with the exception of the finding of advanced generalized atherosclerosis.
Classified as miscellaneous deaths are an early
death from an upper gastrointestinal hemorrhage and 4
late deaths, a fatal upper gastrointestinal hemorrhage, a
malignancy, a suicide, and an automobile accident.
Both gastrointestinal hemorrhages occurred in patients
receiving aspirin and corticosteroids, and postmortem
examinations failed to reveal mesenteric vasculitis. The
malignancy, a squamous cell carcinoma of the tongue,
appeared after 10 years of immunosuppressive drug
therapy.
Table 3. Infection as a contributing cause of death in patients with lupus nephritis
Year of
death
Primary cause
of death
Cytotoxic drugs
received
1967
1967
1970
1972
1974
Renal failure
Renal failure
Renal failure
Renal failure
CNS lupus
No
Cyclophosphamide
Cyclophosphamide
Azathioprine
No
1974
I975
1976
Pulmonary embolism
Renal failure
Renal failure
No
Cyclophosphamide
Cyclophosphamide
Organisms
Pseudomonas aeruginosa
Pseudomonas aeruginosa
Escherichia coli
Staphylococcus aureus
Escherichia coli, Pseudomonas aeruginosa,
Staphylococcus aureus
Pseudomonas aeruginosa
Escherichia coli
Mixed gram negative
Involvement
Bacteremia
Bacteremia
Pneumonia
Bacteremia
Pneumonia
Bacteremia
Pneumonia
Colonic perforation
MORTALITY IN LUPUS NEPHRITIS
767
Table 4. Sudden deaths in patients with lupus nephritis
Yearof
death
Ageat
death
I969
50
1972
1972
45
3I
1973
45
I976
54
IY76
40
Cardiovascular history
Hypertension, 3" atrioventricular
block, pacemaker implanted
Hypertension, angina pectoris
Hypertension;3 documented past
myocardial infarctions
Mitral insufficiency, history of
myocardial infarction
Hypertension, angina pectoris,
history of PAT*
Hypertension, past myocardial
infarction and pulmonary embolism
Postmortem findings
Not done
Not done
Acute myocardial infarction
Acute fibrinous pericarditis,
Libman-Sachs endocarditis
Not done
Acute myocardial infarction
PAT = paroxysmal atrial tachycardia.
Thirty-one of the 68 persons whose deaths are
here reported had had renal biopsies (Table 5 ) . Of the
24 patients exhibiting diffuse proliferative glomerulonephritis, renal failure developed in 13 with death occurring at a median of 62 months from the onset of renal
disease. In this group, 11 nonrenal deaths resulted earlier with a median survival of 14 months. Only l of the
7 patients with other forms of glomerular pathology on
biopsy died of renal failure. On renal biopsy obtained 3
years prior to death, this patient showed focal proliferative nephritis; a postmortem examination was not performed.
DISCUSSION
In this series, renal failure, infections, and vascular events accounted for 81% of the deaths in patients
with lupus glomerulonephritis. Deaths due to renal failure occurred at a steady rate during the years after the
recognition of renal disease. In the early period after the
onset of nephritis, active lupus and infectious deaths
were prominent and accounted for 74% of early nonrenal failure deaths. After more prolonged renal disease,
vascular events emerged as the predominant cause of
late nonrenal deaths (69%). This bimodal mortality pattern of early deaths due to active lupus and infection
Table 5. Causes of death in patients with renal biopsies
Primary cause of death
~~
Glomerular biopsy
classification
Diffuse proliferative
Other*
Number
Renal
failure
Other
24
7
13
1
11
6
* Membranous, focal, mesangial, and minimal proliferative nephritis.
and late deaths due to vascular events has been reported
by Urowitz et a1 (3).
Although a retrospective study of deaths cannot,
by its nature, prove an aspect of disease to be a specific
predictor of death, predictors for a particular cause of
death can be ascertained. The classification of glomerular pathology by light microscopy as suggested by Baldwin (9) was found helpful in this regard. As also shown
by Cheatum et a1 (15), renal failure was the most frequent cause of death in persons in whom a renal biopsy
had established a diagnosis of diffuse proliferative glomerulonephritis. In contrast, renal failure was the cause
of only one death in patients with other forms of nephritis. That patient with focal glomerulonephritis presumably suffered the now well recognized progression
from focal to diffuse nephritis (9,16).
Sepsis has always played a leading role as a
cause of death in SLE and prior to the availability of
antibiotics and corticosteroids was the major cause of
mortality. In our series, terminal infections, either primary or secondary, were associated with 28% of the
deaths. Septicemias from unknown portals of entry and
pneumonias were the predominant infections, and gram
negative organisms were the most common offenders.
All patients but one were taking corticosteroids and the
terminal creatinine was greater than 2 mg/dl in 12 of 19
patients. All cases of Pneumocytis carinii pneumonia occurred after cytotoxic drug therapy with a bacteriologic
setting of a mixed pulmonary infection including bacteria, fungii, or viruses.
The prevalence of vascular phenomena as causes
of death in SLE has increased from 0% in the presteroid
era (1) to 45% in a recent series (3). Vascular diseases including myocardial infarction, pulmonary embolism,
and hypertensive cerebrovascular accidents were responsible for 25% of the deaths in this series and were
KARSH ET AL
768
Table 6. Causes of death in SLE
Percent of deaths due to:
SLE series
Years
Ropes ( 5 )
193249
1949-66
1940-54
1950-55
1956-62
1963-73
1957-68
1968-73
1963-71
1954-77
Total
Harvey (6)
Dubois (4)
Urman (2)
Estes (7)
Karsh
Number
of patients
Number
of deaths
Renal
failure
Infection
Active
SLE*
Vascular
eventst
Miscellaneous
and unknown
60
82
I38
43
39
38
57
49 1
100
209
I56
I50
428
92
49
19
53
94
14
36
24
26
36
14
27
42
36
29
40
21
40
16
12
19
22
16
13
13
37
31
16
34
20
19
49
21
24
8
4
5
3
6
7
11
10
21
5
7
17
18
25
37
12
21
I714
584
28
19
23
8
22
17
29
Includes serositis, myocarditis, pneumonitis, and CNS lupus.
t Includes myocardial infarction, sudden death, pulmonary embolism, and cardiovascularaccident.
encountered late in the course of SLE renal disease. Our
categorization of these three conditions together does
not imply a common vascular pathology. Damage to
vascular endothelium in patients with SLE can be
caused by active vasculitis, hypertension, nephrotic syndrome, and hyperlipidemia and as a result of the prolonged administration of corticosteroids (17-2 1).
An increased frequency of thromboembolic
events has been reported in patients with the nephrotic
syndrome (21-25). In this series 6 deaths were attributed to pulmonary embolism and 4 of the 6 patients
were nephrotic at the time. The mechanisms and sites of
thrombii formation in these patients are unknown. Increased coagulability (26) and platelet adhesiveness (27)
are prevalent during the nephrotic syndrome and could
certainly predispose to thrombotic events. The recent
demonstration of renal vein thrombosis and pulmonary
emboli in nephrotic lupus patients suggests a potential
site of formation (28,29).
We are unaware of reports of specific causes of
death confined to SLE patients with nephritis. In order
to compare our data with those of others we have included all 94 known deaths (68 deaths here detailed, 5
in patients without renal disease, and 21 in whom the
cause of death is unknown) among our 428 patients
(Table 6).
Several observations can be made concerning
mortality in patients with SLE. First, our experience
corresponds rather closely to that of other series which
were nor virtually confined to renal disease. Second, the
patterns of mortality in SLE patients have remained relatively constant through the last 30 years. Deaths from
renal failure, particularly in patients followed from the
I
mid 1950s, constitute the principal cause of death. Despite advances in the isolation of infectious agents and
antibiotic therapies, the prevalence of infectious deaths
has remained rather constant between 10 and 20%. This
has been associated with a shift from more easily
treated gram positive infections to resistant gram negative opportunistic organisms. And finally more recently
cardiovascular events appear to be increasing in frequency with the complications of atherosclerotic disease
developing in young SLE patients.
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