Renal failure, dyspnea and anemia in a 57 year old woman

CLINICOPATHOLOGIC CONFERENCE

Renal Failure, Dyspnea and Anemia in a 57 Year Old Woman

Stenographic reports of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal. Members of the Departments of Internal Medicine, Radi- ology, and Pathology of the Washington University School of Medi- cine participate jointly in these conferences. Kenneth M. Ludmerer, M.D., and John M. Kissane, M.D., are the editors of this feature.

A 57 year old black female was admitted to Jewish Hospital of St. Louis

February 13, 1980, with dyspnea and anemia. For many years, the patient had had severe hypertension. Six years

prior to admission, administration of guadethidine and high doses of

hydralazine and alpha-methyldopa was begun for this problem. Despite

treatment, symptoms of congestive heart failure developed, and di-

goxin therapy was initiated. Two years prior to admission, arthralgias

developed, particularly in the shoulders, elbows and hands. The

erythrocyte sedimentation rate (ESR) was normal, and antinuclear

antibodies (ANA) were absent. Naproxen, 200 mg four times a day,

was prescribed but did not relieve her symptoms. Six months prior to

admission, during a routine outpatient visit, her hemoglobin level was

11.5 g/d1 and her serum creatinine 1.2 mg/dl. Results of urinalysis at

that time were normal. Two weeks prior to admission, she noted

lightheadedness and dyspnea on exertion. She was seen again by her

physician, who found her hemoglobin level to be 5.5 g/dl, and hospi-

talization was promptly arranged. She denied overt blood loss, easy bruising, fever, sweats, chest pain, alopecia or photophobia.

Physical examination on admission revealed a temperature of

37.5’C, a blood pressure of 120/70 mm Hg without orthostasis, a pulse rate of 76/min and a respiratory rate of lG/min. The conjunctivae

were pale and the sclerae nonicteric. No retinal hemorrhages were

seen. The lung examination was noncontributory. The cardiac apical

impulse was enlarged and displaced to the left. The first and second

heart sounds were normal; a prominent fourth heart sound was heard;

and a grade 316 systolic murmur was present along the left sternal

border. The spleen was palpable 2 cm below the left costal margin. Rectal, pelvic, joint and neurologic examinations were unremarkable. No occult blood could be detected in the stool.

Laboratory work on admission was remarkable for a hemoglobin level of 5.0 g/dl, a hematocrit value of 16.1 percent, a mean corpus-

cular volume of 72 p3, a white blood cell count of 7,000/mm3, a reticulocyte count of 6.2 percent and a platelet count of 248,000/mm3. The urinalysis revealed a pH of 5, 2+ protein, moderate blood and red cell casts. The serum electrolytes were within normal limits. Other

test results included a glucose level of 108 mg/dl, creatinine level of

878 November 1981 The American Journal of Medicine Volume 71


TABLE I Flow Sheet of Selecied Hematologic Parameters

Reticulocytes WBC Platelets Date (;I) (rzl) (percent of RBC) (mm3) (mm3)

- 6 months 11.5 2713 (admission) 5.0 l6.; 62 7,000 352:;oo +3.5 units of packed

cells 2115 10.0 32 2117 9.1 27.5 23 5,&o : : : 2/19 7.5 26.3 248,000 i- packed cells (?) 2/21 13.2 40.1 1.2 6,700 318,000 procedure 2123 10.4 31.6 11,400 409,000

2/13 Smear: rouleaux, moderate microcytosis and some hypochromia. Differential: 63 neutrophils, 6 band forms, 5 eosinophils, 22 lymphocytes, 2 monocytes, 1 basophil, 1 metamyelocyte. HbAs 6.2 percent.

2/16 Fetal Hb 5.0 percent of total; bilirubin 1.5 mg/dl. 2/23 Bone marrow: adequate cellularity with normal morphology and some decrease in

hemoglobinization of RBC precursors: stainable iron absent. Differential: 6 percent lymphocytes and 84 percent neutrophils.

4.9 mg/dl, urea nitrogen level of 56 mg/dl, calcium level

of 8.5 mg/dl, phosphate level of 4.6 mg/dl, total bilirubin level of 0.7 mg/dl, albumin level of 3.8 gm/dl and total

protein level of 7.6 g/dl. Additional studies demonstrated

a thyroxine level of 7.5 pgldl, iron level of 20 pg/dl,

total iron binding capacity of 279 pg/dl, lactic dehy-

drogenase (LDH) level of 268 IWL, and negative results

of rapid plasma reagin test. A chest x-ray showed car-

diomegaly with clear lung fields. The electrocardiogram

(ECG) revealed left ventricular hypertrophy. The ESR

was 110 mm/hr, latex rheumatoid factor was negative, and ANA was positive at a 1:320 dilution with homo-

geneous and speckled patterns. The direct Coombs’ test

gave weakly positive results while results of the indirect

Coombs’ were negative. Urinary protein excretion was

1.1 g/24 hr, and the creatinine clearance was 15 ml/

min. The total hemolytic complement was 80 units

TABLE II Flow Sheet of Selected Renal Parameters

Date 24-hr Urine

Total Protein Urinalysis

-6 months 2113 2114 2115

2116 2/20 2124 2126

1.2 Norrhal 4.9 ‘56 “. 1.1 gr

Many RBCs Many RBCs, WBCs,

probable red cell casts

4.8 7.2 ‘79 9.2 96 8.5 120

2.27 8.3 . CLINICAL DISCUSSION

2/ 18 Ultrasound: normal-sized kidney. 2/21 Tcggm renal scan: symmetrically reduced renal perfusion

without obvious areas of infarction.

(normal, 70 to 115) the C3 was 85 mg/dl (normal, 76

to 146) and the C4 was 34 mg/dl (normal, 14 to 41).

Anti-Kell antibody was detected in the serum. The serum

haptoglobin level was normal; hepatitis B surface an-

tigen was negative but the surface antibody was posi-

tive. The Raji cell assay for immune complexes was

elevated 17 standard deviations above the mean. Cry-

oglobulins were not measured.

Therapy was initiated with a transfusion of 4 units of

blood, and the dyspnea markedly improved. Hydralazine

was discontinued with resultant stabilization of the blood

pressure at 180180 mm Hg. During the first week of

hospitalization, the patient experienced persistent

fevers between 38’ and 39OC. Urine and blood cultures

showed no bacterial growth. Findings on proctoscopy

were normal. A barium enema revealed diverticulosis.

An upper GI series showed a peptic deformity of the

antrum and pylorus that was subsequently found by

endoscopy to contain an active ulcer. Renal sonography demonstrated the kidneys to be of normal size with no

evidence of obstruction. A technetium scan of the

kidneys revealed symmetrically reduced renal perfusion

without obvious areas of infarction. A repeated direct

Coombs’ test, while the patient was still receiving

methyldopa, was negative. During this time, the serum creatinine rose to 9.2 mg/dl and the urea nitrogen to 120

mg/dl. The hematocrit value remained at approximately

29 percent. On the ninth hospital day a diagnostic procedure was

performed.

Dr. John Atkinson: Tables I and II contain more de-

tailed flow sheets of the hematologic and renal parameters then provided in the protocol. These will be

November 1981 The American Journal of Medicine Volume 71 877

RENAL FAILURE, DYSPNEA AND ANEMIA

useful to us later. Right now, I would like to discuss

certain aspects of the patient’s history.

First, she had had severe high blood pressure for six

years. On admission, her antihypertensive medications

consisted of guanethidine (15 mg four times a day),

hydralazine (100 mg four times a day), alpha-methyl-

dopa (500 mg four times a day) and propranolol(l0 mg

four times a day). We have no record of her blood

pressure readings during this time, but it should be noted

that she was under a physician’s care and that the hy-

pertension was carefully monitored and treated.

Second, congestive heart failure developed in 1978,

and digoxin and a diuretic were administered. We do not

know the basis for this diagnosis. I suspect that her

physician believed she had hypertensive cardiovascular

disease. Since subsequently we will be entertaining the

diagnosis of systemic lupus erythematosus (SLE), the possibility of pleural-pericardial and myocardial in-

volvement secondary to this disease becomes an al-

ternative explanation of her heart failure.

Third, arthralgias in her shoulders, elbows and hands

developed two years before admission. The location of

her symptoms differed from that of the usual “aches and

pains” syndrome seen commonly in outpatient prac-

tice-a syndrome that much more often involves the

low back, knees and hips. Therefore, her complaints,

together with the knowledge she was taking hydralazine,

raise the specter of an underlying rheumatic disease.

Her physician apparently had similar thoughts and or-

dered, in my opinion, the two best screening tests in this situation: an ESR and an ANA test. The results of these

tests were both normal, and at the time it was appro-

priate not to undertake further evaluation. Despite

medication, however, her arthralgias persisted.

Fourth, she was lightheaded for at least two weeks

prior to seeing her physician. This delay in seeking

medical consultation may explain the apparent absence

of blood in her stool. After a major upper gastrointestinal

bleed, blood can be detected in the stool for no longer

than one week.

Fifth, some of her physical findings on admission are

surprising. Despite a hematocrit value of 16 percent,

her blood pressure was normal and there was no orthostatic fall. In addition, on repeated examinations her

pulse rate was only 76/min, her respiratory rate lG/min,

and her temperature 37.5’C. The propranolol may have

slowed her pulse rate, but it should not have prevented an orthostatic fall. Thus, the patient’s cardiovascular

status was surprisingly well compensated, especially in view of her prior history of cardiomegaly and congestive heart failure.

Sixth, the absence of retinal hemorrhages represents an important negative finding. If present, such hemor-

rhages could have resulted from either the severe anemia or hypertension. Since the fundus contained no

findings compatible with long-standing hypertension,

it becomes much less likely that high blood pressure

caused her renal and cardiac problems.

Seventh, a cardiologist who examined the patient the

morning after admission noted the presence of a loud

S-3 gallop, a left ventricular heave, a wide pulse pres-

sure, and Quincke’s and Corrigan’s pulses. Accordingly, he suggested that she had high output failure from se-

vere anemia superimposed upon probable hypertensive

heart disease.

Eighth, in addition to the exceedingly low hematocrit

level that prompted hospitalization, the patient’s serum

creatinine was also notably abnormal on admission. Six

months previously, her creatinine level had been 1.2

mg/dl and results of urinalysis normal. The deterioration

in renal function, too, demands explanation.

Ninth, I reviewed previous chest radiographs as well as her ECGs. In 1977, the cardiac silhouette was nor-

mal. In February 1980, the chest x-ray revealed car-

diomegaly with left ventricle predominance. The lung

fields at that time were clear. Although her admission

ECG met the Estes criteria for left ventricular hyper-

trophy, an echocardiogrm that hospitalization was within

normal limits.

Last, although her temperature was normal on admission, she was febrile throughout the remainder of

her lo-day hospitalization. Appropriate cultures were

negative.

As I evaluate the case, we have several tasks. Most

importantly, we need to determine the cause of the anemia and renal failure. In addition, we must construct

a diagnosis that accounts for all patient’s problems.

Finally, we need to predict the procedure that was

performed and the pathologic findings that were noted. We will address these issues in order.

Before turning the discussion over to Dr. Chaplin, I would like to make a few points concerning her anemia.

We know that six months prior to admission she had a

hemoglobin level of 11.5 g/dl; however, by February

1980, severe anemia had developed. On admission, the

differential diagnosis was principally between hemolysis

and blood loss. On the basis of the relatively low retic-

ulocyte count, the normal bilirubin level, a blood smear inconsistent with ongoing hemolysis and normal LDH

and haptoglobin levels, the house staff correctly as-

sumed that the picture was incompatible with acute

hemolysis. Within 24 hours of admission she had re-

ceived 3.5 units of packed red blood cells, with subsequent improvement in her sense of well-being and

with the anticipated rise in hematocrit level. However, over the next three days, without evidence of blood loss,

the hemoglobin level dropped from 10 to 7.5 g/dl. I would like Dr. Chaplin to address the problem of the

post-transfusion drop in hemoglobin as well as to discuss the cause or causes of the anemia that was

present on admission. Dr. Hugh Chaplin: The hematologic problems of this


case are difficult and controversial. Because time is

limited, I would like to focus on the four major questions

posed by our patient: (1) Does our patient have an

underlying chronic, possibly inherited, hematologic

abnormality? (2) Are her hematologic findings secon-

dary to any of the drugs she was taking? (3) What was

the primary cause of her severe anemia on admission?

(4) Could she have had a delayed hemolytic transfusion reaction?

Regarding the possibility of an underlying chronic

inherited hemolytic anemia, several points are pertinent:

the moderate anemia six months prior to admission; the

microcytic, hypochromic indices at this admission; a

hemoglobin A2 value of 6 percent: and a fetal hemoglobin value of 5 percent on one occasion prior to

transfusion. In addition, she had mild splenomegaly. I

believe these findings suggest the diagnosis of thalas-

semia minor, and I believe she had this condition

throughout her life, presumably without having suffered

any significant consequences. I believe our patient also

had superimposed iron deficiency on the basis of several findings: her low serum iron level, the slightly ele-

vated total iron binding capacity and the absence of iron

in the bone marrow. It is interesting that the elevated

A2 hemoglobin value characteristic of thalassemia

minor may fall to normal if superimposed iron deficiency

develops. In today’s case, however, the elevated A2

hemoglobin persisted, a phenomenon that occurs in at

least half the patients with thalassemia minor in whom

iron deficiency develops.

Next, we must consider the possible role of drugs in

the development of her anemia. The three most likely

pharmacologic culprits are methyldopa, hydralazine and naproxen. Methyldopa must always be considered when

severe anemia develops in patients taking the drug, but in this case I believe it can be totally exonerated. In

cases of methyldopa-induced hemolytic anemia, the

Coombs’ test result invariably is very strongly positive

and remains so for months after the drug is discontin-

ued. In today’s case, the Coombs’ test on admission

gave only weakly positive results, a fact that eliminates

methyldopa as an offending agent. The weakly positive

Coombs’ test result might have been related to the hy-

dralazine because this phenomenon occurs as part of the lupus-like syndrome associated with the drug. In

such cases, the positive Coombs’ result can be shown to be caused by the binding of the third component of

complement to the red blood cells. However, it is highly

unlikely that hydralazine caused our patient’s severe

anemia. The lupus-like syndrome associated with hy-

dralazine and other drugs is much more often characterized by a weakly positive Coombs’ test result than

by frank, brisk hemolysis. In those rare cases when hydralazine produces significant hemolysis, the he-

molysis results from a drug/anti-drug immune complex mechanism. As a consequence, the Coombs’ result is


strongly positive for complement, which was not found

in today’s case. Furthermore, without good evidence

for hemolysis-her admission bilirubin and haptoglobin

levels were normal-the likelihood that either methyl-

dopa or hydralazine is implicated decreases even more. Naproxen causes an abnormality in platelet aggregation

and a modest elevation in bleeding time, both of which

may facilitate hemorrhage, especially when underlying

gastrointestinal disease is present. Therefore, I think

the naproxen may have contributed to blood loss from

our patient’s gastrointestinal tract, which I believe was

the primary cause of her very low hemoglobin level on

admission. The hemorrhage almost certainly occurred

from the channel ulcer that was demonstrated radio-

graphically. The bleeding had stopped by the time of

admission, and her reticulocyte response was subop-

timal for a hemoglobin level of 5 g/dl. However, such

a poor reticulocyte response is readily explainable on

the basis of iron deficiency, chronic illness, fever and

rapidly progressive renal failure.

Finally, we must consider the possibility of a delayed

transfusion reaction. Initially, this woman’s serum was

not difficult to cross-match, and she received the first

3 of her 4 units of blood without incident. During the

subsequent 96 hours, however, the hemoglobin level

dropped from 10 g/dl to 7.5 g/dl; and 48 hours after her

transfusions had ended, her bilirubin level had risen to 1.5 mg/dl. Following transfusion, the bilirubin can rise

simply from the destruction of nonviable cells that are

always present to some extent in transfused blood.

However, this mechanism occurs within the first 8 hours

after the cessation of the transfusion and hence does

not explain an elevation of the bilirubin 48 hours later. Thus, I believe the patient had a mild delayed transfusion

reaction. Enhancing this possibility is that anti-Kell

antibody, which had not been demonstrable earlier, was

subsequently clearly evident in her serum. These ob-

servations suggest the stimulation of alloantibody in a

previously sensitized woman. Our patient was para-IX,

gravida-IX; it is very likely that an earlier pregnancy

caused her initial anti-Kell sensitization. Since Kell-

positivity is found in approximately 1 of 10 units of

blood, it is quite possible that at least 1 of the 4 units she

received contained that antigen. In summary, I think our patient had underlying tha-

lassemia minor. Although she was taking certain drugs

that can cause hemolytic anemia, I do not believe they were responsible for the severe anemia in her case.

Rather, I believe her anemia arose from gastrointestinal

blood loss that was possibly aggravated by the bleeding diathesis produced by naproxen. I think she also had a

mild hemolytic transfusion reaction secondary to re- stimulation of anti-Kell antibodies which would have

originally been provoked during one or more of her

pregnancies. Dr. Atkinson: Thank you. A likely source of the gas-



trointestinal bleeding was found, and no further bleeding

occurred in the hospital. Thus, despite a rather complex

hematologic picture on admission, a successful eval-

uation was completed within a few days. Hence, let us

now analyze the renal failure (Table II).

On admission, the patient displayed elevated urea

nitrogen and creatinine levels. Since she gave no history

of previous renal disease but was known to be hyper-

tensive, her physicians initially made the reasonable

assumption that her renal impairment resulted from

nephrosclerosis. However, several factors militated

against the diagnosis of hypertensive renal disease: a

normal serum creatinine six months prior to admission,

a well-controlled blood pressure during the previous six

months and the absence of end organ damage in the

eye grounds. The initial results of urinalysis appeared on the chart

the evening of February 14 or the morning of February

15. The urinary sediment contained protein and nu-

merous red blood cells. No casts were seen. On the

evening of February 15, a temperature of 392OC de-

veloped. At that time, an intern carefully evaluated the

possible causes of her fever. His urinalysis documented

a sediment laden with numerous red blood cells and, in

all likelihood, red cell casts. Since the creatinine level

on February 16 had not changed from that on admission,

the focus of her evaluation remained on the anemia. However, five or six days later, her renal function began

to deteriorate rapidly, and the direction of the work-up turned toward the kidneys. A renal scan and ultrasound

study both demonstrated normal kidney size. The renal scan also showed symmetrically reduced function in

both kidneys. Dr. Martin will now present his analysis

of the renal failure.

Dr. Kelvin Martin: In order to evaluate a patient with

new renal failure, it is useful to consider the main ne-

phrologic syndromes [I]. Acute nephritis denotes an

acute inflammatory process in the kidney, usually in the

gfomeruli, that is manifested by renal failure, proteinuria

and the presence of blood or red cell casts in the urinary

sediment. The presentation of today’s patient clearly

fits this syndrome. An additional consideration in our patient is hypertensive renal disease, which was orig-

inally believed to be the cause of her renal failure. Al-

though hypertensive nephrosclerosis commonly pro-

duces renal failure and urinary findings similar to those

seen in today’s patient, the normal retinal examination makes hypertension highly unlikely as the cause of her

rapidly progressive renal failure. Since this patient’s renal failure developed over six

months, the major consideration is subacute nephritis. Since casts may disappear with storage, I wish to em-

phasize the importance of frequently examining the sediment in freshly voided urine rather than sending

specimens to the laboratory. Renal biopsy is indicated

in such cases, and this presumably was the procedure

performed on our patient. I would anticipate that biopsy

revealed proliferative glomerulonephritis. Dr. Atkinson: We now need to construct a differential

diagnosis. The most likely possibility by far is SLE. A

more difficult issue to resolve is whether the SLE is

idiopathic or drug-related. Another possibility, quite

remote, is that she had idiopathic rapidly progressing

glomerulonephritis of an immune complex type with the

positive serologic studies occurring incidentally secondary to the hydralazine. Although I cannot rule out this

possibility, I am going to devote the rest of my discus-

sion to SLE.

In complicated cases such as this one, it is useful to

list points for and against the diagnosis of SLE. Several

features in the case favor that diagnosis: (1) a two-year

history of arthralgias of the upper extremities unre- sponsive to nonsteroidal anti-inflammatory drugs; (2)

an unexplained fever; (3) splenomegaly (although, as

Dr. Chaplin suggested, this could have resulted from the

heterozygous ,&thalassemia); (4) rapidly progressive nonobstructive renal failure with an active sediment,

which strongly suggests glomerulonephritis; (5) a pos-

itive ANA result, which admittedly could have been an

incidental finding secondary to the hydralazine; (6) a

positive test for circulating immune complexes, as detected by the Raji assay, with very high levels that are

frequently seen in SLE but only occasionally in other

diseases: (7) a diffuse polyclonal increase in IgG; and

(8) a very high ESR. Although none of these findings

alone is definitive, together they argue strongly for an

immune complex type of illness-probably SLE, either

of drug-induced or idiopathic type.

A few points weigh against SLE. The patient had no

involvement of the skin or mucous membranes, a

finding present in about 90 percent of patients with that

illness. Indeed, dermatologic findings account for the

majority of the 14 criteria used by the American

Rheumatism Association to diagnose SLE clinically. She

had normal serum complement levels, whereas ap-

proximately two-thirds of patients with renal involve-

ment in SLE have reduced levels. She had no rheuma-

toid factor and a normal partial thromboplastin time, but

these are abnormal in only approximately one-third of patients with SLE. She also had no thrombocytopenia

or leukopenia, both common hematologic manifesta-

tions of SLE. Obviously, in the appropriate clinical setting, none of these points rules out the diagnosis of SLE, and I still believe she had this disease. Assuming

this to be the case, we must next consider whether she

had drug-induced SLE secondary to hydralazine or idiopathic SLE.

Our knowledge of hydralazine-induced SLE largely results from studies performed at Washington University under the direction of Dr. Mitchell Perry. We are fortu-


nate to have Dr. Perry with us today, and later in the

discussion he will present his analysis of the present

case. Dr. Perry, as director of the Washington University

Hypertension Unit, began treating hypertensive patients

with hydralazine in 1952 when this agent first became

available. At that time hydralazine was one of the few

effective and reasonably well tolerated drugs for high

blood pressure. In 1953, he and his co-workers published the initial description of the “hydralazine syn-

drome” [ 21. Several of his patients had development

of a clinical syndrome consisting of such constitutional

symptoms as fatigue, fever, malaise, asthenia and arthralgias and arthritis and pleurisy. These patients also

had characteristic laboratory abnormalities, including

elevated gamma globulin levels, a high ESR and a positive LE preparation. At that time, SLE was consid-

ered a rare disease, and serologic tests to assist with

the diagnosis were just becoming available. Several

other reports around the same time confirmed these features of the illness [3,4]. Dr. Perry then initiated a

long-term study of these patients, and I will summarize

four of his most important publications [5-81.

In 1965, he and his co-workers described a number

of additional clinical and serologic features of the hy-

dralazine syndrome [ 51. The syndrome developed in

about one-fifth of the patients who had taken more than

200 mg of hydralazine per day for several years. Anti- nuclear antibodies could be found in approximately 60

percent of these patients. The illness rarely occurred

in blacks, although blacks who had the syndrome also had antinuclear antibodies. Clinically, the syndrome

could not be distinguished from idiopathic SLE. How-

ever, hydralazine-induced SLE only rarely involved the

central nervous or renal systems. In addition, the hy-

dralazine syndrome was generally characterized by

absent cryoglobulins and normal complement deter-

minations. Severe high blood pressure prompted re-

institution of the drug in several patients, and the syn-

drome again developed in about two-thirds of these patients.

In 1970, Dr. Perry made another very interesting

observation [6]. Dr. Perry and his colleagues examined

the ability of 57 patients on maintenance hydraiazine

therapy to acetylate drugs. Acetyl transferase-N is a

hepatic enzyme important in the catabolism of a number

of drugs, including procainamide and hydralazine. The

rate of hepatic acetylation can be determined by mea- suring urinary concentations of a sulfonamide following

intravenous administration of the drug. About 50 percent

of both normotensive and hypertensive persons are fast

acetylators. Dr. Perry evaluated the acetylation status of 57 patients who had been taking hydralazine at a minimal dose of 200 mg a day for a period of one to

fifteen years. Thirty-one of 57 patients were ANA-

positive. Of the slow acetylators, more than half were

cLlNtc0PATH0L00i~ CONFERENCE

ANA-positive; of the fast acetylators, nine of 24 became ANA-positive. Dr. Perry also showed that ANA was

found in the slow acetylators sooner than in the fast

acetylators. The most important point in the study was

the observation that of the 12 persons in whom SLE

developed, all were slow acetylators and ANA-positive. Thus, hydralazine-related SLE usually occurs in patients

on long-standing, high doses of the drug who have

positive ANA and who are slow acetylators.

A few years later Dr. Bevra Hahn, in collaboration

with Dr. Perry and other colleagues, examined the im-

munologic response of these patients to hydralazioe

[7]. They showed that patients with this syndrome

produced antibodies specific for both hydralazine and

certain nuclear constituents. In addition, they showed that the lymphocytes of these persons underwent

modest but definite transformation in response to hy-

dralazine. Patients with idiopathic SLE, in contrast, did

not have antihydralazine antibodies. More recently,

another group demonstrated that ANA in drug-induced

SLE were quite specific, being primarily directed to

histones, the basic nuclear proteins associated with

DNA [9]. In idiopathic SLE, only one-third of the patients

had antibodies to histones. In contrast, 23 of 23 patients

with drug-induced SLE possessed such antibodies.

Moreover, patients with the drug-induced syndrome did

not have antibodies to native DNA. Some data in the literature have suggested that hydralazine, a highly re-

active molecule, may form physicochemical bonds with

DNA-histones [9]. In this way, hydralazine could be

acting like a hapten. This could explain why persons

with the drug-induced syndrome have antibodies to

hydralazine, histones, and to a hydralazine-histone

complex. In summary, the initial description and most

of the advances in our understanding of this syndrome

have resulted from. Dr. Perry’s work at Washington

University. His 20-year experience with hydralazine-

inducedSLE has been reviewed in this journal [8].

Drug-induced SLE commonly occurs in two principal clinical set$ngs. One is that of today’s patient-hya

pert&nsive persons who have been taking hydralazine

for several years. The illness begins insidiously with arthralgias, followed by arthritis and constitutional

symptoms. The second setting involves patients re-

ceiving procainamide for control of ventricular pre-

mature beats. After several months, they can have a syndrome of arthralgias and arthritis (particularly in the

shoulder girdle), fever and pleural-pericardial mani-

festations that easily mimic other conditions such as the

postmyocardial infarction syndrome, pulmonary em-

bolus, congestive heart failure and recurrent coronary pain. In both forms of drug-induced lupus, central ner-

vous system and renal involvement are almost invari-

ably absent. Serologic studies in both situations generally demonstrate ANA, but normal complement levels,



no cryoglobulins and no antibodies to native DNA. In

both cases, the disease usually remits within a few

months after the drug is stopped.

To reinforce some of these comparisons, I would like

to mention a review by Dubois et al. [lo]. They studied

33 patients with procainamide-induced lupus, 50 pa-

tients with hydralazine-induced lupus, and 500 patients

with idiopathic lupus. All three groups demonstrated a

high incidence of fever, arthralgias and arthritis. Pleuritis

and pericarditis occurred frequently in the patients taking procainamide. In the two groups with drug-in-

duced lupus, skin manifestations occurred less com-

monly and central nervous system and renal involve-

ment were distinctly unusual. Dubois also found a low

incidence of adenopathy and gastrointestinal complaints

in the patients with the drug-induced syndrome, but I

have not found these latter items useful in distinguishing

idiopathic from drug-related disease.

With this background, we can now summarize the

information for and against drug-induced SLE in today’s

patient. Strongly against the diagnosis is this patient’s

race. As mentioned, only in rare instances has hydralazine-induced SLE developed in black persons. Renal

failure, although described, is also quite unusual in hy-

dralazine-induced lupus. For example, in the Wash-

ington University experience, renal involvement pos-

sibly occurred in only two patients [8]. Of note, a con-

trary report from the Mayo Clinic suggested that renal

disease develops in 10 to 25 percent of patients with

hydralazine-induced lupus [ 111. However, this series

must be taken lightly because it was not clearly estab-

lished that the subjects had hydralazine-induced SLE,

in contrast to the alternative possibility that they had

already contracted lupus and were taking hydralazine

for secondary hypertension. Unfortunately, we do not have certain laboratory in-

formation that would help us distinguish between hy-

dralazine-induced and idiopathic lupus. For example,

the presence of antibodies to native DNA would militate

against drug-induced SLE. If we knew our patient were

a fast acetylator, the diagnosis of drug-induced SLE would again be unlikely. (In this case, however, testing

her acetylator staus by the “sulfa method” during the

last admission would have been impossible because

of her renal failure.) The most helpful factor, however,

would be knowledge of the clinical outcome after the

drug was stopped. If, after hydrajazine was discontinued, the clinical syndrome resolved, the ANA titer progres- sively decreased and no further steroid therapy were required, then I would assume that the clinical picture

was drug-induced. Of course, such a sequence of

events would not eliminate the possibility that the patient

had idiopathic SLE that was exacerbated or induced by hydralazine [4,8,10-131.

Next, we need to predict the procedure performed and the likely pathologic findings. Kidney biopsy was

undoubtedly the procedure undertaken since she had

an active urinary sediment with rapidly progressive renal

failure of unknown cause. The creatinine level reached 9.2 mg/dl on the seventh day of hospitalization. In view

of this clinical course, I would have probably begun

pulse therapy with corticosteroids even before biopsy

was performed in the hope of stopping or reversing the

process. While reviewing the chart, I found some ad-

ditional reasons why I think kidney biopsy was per-

formed. First, by the time of the procedure, her hema-

tologic work-up had been completed, and her anemia

had been treated with transfusions. In addition, around the time of the procedure, lymphocytopenia and gran-

ulocytosis developed and she became afebrile-all of

which could have been secondary to the administration

of corticosteroids. Taken together, these observations

make me believe that she underwent kidney biopsy on

the ninth hospital day and probably received a steroid

pulse about the same time.

Dr. David McLain, a former fellow in the Washington

University Rheumatology Division, two years ago began

to study the serologic features of drug-induced lupus.

He has accumulated data on 12 patients and has shared his findings with me. Even in this small series, he has

found patients with drug-induced SLE who have had

cryoglobulins [ 141, immune complexes by Raji assay,

typical lupus anticoagulant and low complement levels.

Other investigators have also reported patients with

drug-induced lupus in which these serologic test results

were positive or abnormal [ 15-181. In most such pa-

tients, however, these serologic tests give normal re-

sults. Indeed, a patient very similar to the one under

discussion today was described in Dr. McLain’s file, and

Dr. McLain had concluded that this person did not have

drug-induced lupus.

Assuming renal biopsy was performed, we must predict the likely pathologic findings. The marked and

rapid deterioration of renal function argues against a

focal proliferative glomerulonephritis, although the

modest proteinuria is compatible with such a histologic

finding. More likely, in view of the rapid course of her

renal disease, she had diffuse proliferative glomerulo-

nephritis, although such patients generally have low

complement levels and detectable antibodies to native

DNA.

In summary, I believe this patient had high blood

pressure, probably idiopathic or essential. She may also have had cardiovascular disease secondary to the hypertension. In view of the negative ANA results in 1978,

I do not believe that smoldering SLE of several years’

duration caused the hypertension. I believe SLE then

developed, which produced her renal failure. I cannot

be sure whether her SLE was hydralazine-induced or idiopathic, but I favor the latter. She also had a pyloric channel ulcer that probably bled several weeks prior to admission and thus contributed substantially to the


anemia. Other factors contributing to the anemia included a chronic inflammatory disease (lupus), renal failure, iron deficiency and fl-thalassemia minor. Dr. Perry, would you please comment. Dr. H. Mitchell Perry: I would disagree with only one of your points. I believe you have overstated the frequency of renal dysfunction as a complication of hydralazine- related lupus. We have seen only one patient in whom acute renal failure could be unequivocally related to hydralazine-related lupus [ 191. In none of our other patients has any causal link been demonstrated between hydralazine-related lupus and renal dysfunction-despite the fact that many hydralazine-treated patients have renal failure either from hypertension or from the underlying renal disease that presumably caused their hypertension. I know of only one other reported case in which hydralazine-related lupus seemed definitely to be implicated as a cause of renal failure [20].

Another feature would make the diagnosis of hydralazine-related lupus unusual in this case: the patient’s race. Of our first 44 cases of hydralazine-related lupus, two occurred in black patients [8], and other investigators have also reported the syndrome in blacks. De- spite these occasional instances, however, drug- related lupus occurs much less frequently in blacks than in whites. In one study, we observed that the risk was almost five times greater in white patients [ 211. Our two black patients with hydralazine-related lupus both had atypical presentations. Each was a woman with “malignant” hypertension, and both women were receiving 750 mg of hydralazine daily. A clinical syndrome consistent with hepatitis developed in the first patient after three months of exposure. In the second, whose very complicated case has been reported [22], marked asthenia developed after 23 months of exposure.

While I have the floor, I would like to make several additional comments about drug-related lupus. First, the protocol indicates that this patient originally had “severe hypertension,” although it does not specify how high the blood pressure. Most of our early patients with hydralazine-related lupus had truly severe hypertension, with “malignant” hypertension in more than half [8].

Second, the protocol described this patient’s hydralazine dosage as “high,” and I have learned that at one time she ingested 400 mg daily. This is a significant dosage; 75 percent of our early patients with hydralazine-related lupus took at least 400 mg of the drug for six months [8]. According to the information provided, this patient had been taking hydralazine for four years when arthralgias developed and for six years when the renal failure appeared. In only one of our 44 patients with hydralazine-related lupus did symptoms develop after more than four years of exposure to the drug. Thus, it is unlikely that her symptoms resulted from hydrala-


zine-related lupus. Our only patient with documented renal failure secondary to hydralazine-related lupus was unusual because of the extreme severity of her hypertension and the high dosages of hydralazine (up to 1 g per day) she received for therapy. That case has been reported elsewhere [ 191.

Third, the protocol indicates that the patient was normotensive at the time renal failure became apparent. In our experience, the blood pressure almost always falls to normal before symptoms of hydralazine-related lupus appear. In addition, the patients generally remain normotensive for at least as long as the hydralazine- related lupus persists [8].

All our patients with hydralazine-related lupus had positive ANA, as did today’s patient; in each case, the positive ANA antedated the development of clinical symptoms [6]. A positive ANA result. however, appears much more frequently than does symptomatic drug- induced lupus in hydralazine-treated patients. For example, hydralazine often induces positive ANA reults in blacks and white “fast acetylators,” although neither group stands much risk of development of hydralazine-related lupus. “Fast acetylators” may require up to 1,200 mg of hydralazine for development of positive ANA, versus the 400 mg that will produce a positive ANA result in 50 percent of “slow acetylators” [6]. Thus, the appearance of a positive ANA does not war- rant the discontinuation of hydralazine, although white “slow acetylators” should receive closer follow-up observation.

Finally, although our patient’s anemia probably does not relate to hydralazine, it is noteworthy that patients receiving large doses of hydralazine initially experience a drop of hemoglobin averaging almost 2 gm/dl without development of hydralazine-related lupus [23]. With severe hydralazine-related lupus, the anemia is even greater, with an average decrease in hemoglobin of 4.5 gm/dl, and we have seen patients with severe hydralazine-related lupus in whom the hemoglobin decreased as much as 7.4 gm/dl. These anemic patients had di- minished red blood cell volume, low serum iron levels and erythroid hyperplasia of the marrow-all suggesting iron deficiency anemia [8].

In summary, I am impressed that renal failure only rarely results from hydralazine-related lupus. The one case we have seen represented an unusual situation in which we were attempting to control severe hypertension with large doses of hydralazine as the sole drug. Thus, I think it unlikely that today’s patient had renal failure secondary to hydralazine. Dr. Atkinson: I appreciate your comments and agree with your analysis of the hydralazine data. The one published study suggesting that renal failure develops in 20 percent of the patients with hydralazine-induced SLE must be interpreted with caution because of the likelihood that many of the patients, in fact, had idio-


RENAL FAILURE. DYSPNEA AND ANEMIA

pathic SLE with hypertension [ IO]. Hypertension occurs

in more than one-third of patients with SLE. Am I cor-

rect, Dr. Perry, in assuming that you believe today’s patient had idiopathic SLE, with hydralazine being either

unrelated to or, at most, an inducing factor in her

SLE?

Dr. Perry: Yes.

PATHOLOGIC DISCUSSION

Dr. John Meyer: Since I do not know the follow-up in

this patient after hydralazine was discontinued, I can

approach the diagnostic problem with some objectivity.

We received a very nice biopsy specimen that showed

some normal glomeruli and others with various degrees

of damage. The specimen showed no evidence of hy-

pertensive damage, but it did contain severe focal crescentic glomerulonephritis with crescents in five of

13 glomeruli (Figure 1). Silver impregnation prepara-

tions showed breaks in capillary basement membranes

and the presence of fibrin and proliferative changes in

Bowman’s space. Some tufts had undergone partial

dissolution, but mesangial and endothelial hypercellu-

larity was minimal. Tubular red cell casts were present.

The electron microscopy showed some focal prolifer-

ative changes in the capillary loop. These were associated with deposits of electron-dense granular mate-

rials in the mesangium (Figure 2). However, in the two

glomeruli that were examined by electron microscopy, we did not see any subendothelial electron-dense de-

posits typical of those in severe proliferative lupus

nephritis. The mesangium also contained a few neu-

trophilic leukocytes. The immunofluorescent findings

included the presence of granular glomerular basement membrane and mesangial deposits of IgG that were of

2+ to 3+ intensity. Lesser amounts of IgM were

present. Strangely, no C3 was detected, and IgA de-

position was essentially absent.

The differential diagnosis of crescentic glomerulo-

nephritis with immune complexes includes several

entities. We have no evidence of a post-infectious

streptococcal or staphylococcal glomerulonephritis or

of any other type of bacterial infection. We do not have

the concomitant findings of Henoch-Schonlein disease.

Necrotizing vasculitis can be excluded because we

found no vasculitic changes in the biopsy specimen and

because she did not have any other clinical features to

suggest such a diagnosis. Neoplasms in association

with mixed cryoglobulinemia can produce glomerulitis,

but in this case the neoplasm would have to be occult.

She definitely did not have the marked mesangiopro-

liferative changes and capillary basement membrane

duplication characteristic of membranoproliferative

glomerulonephritis type 1. Elimination of these types

of crescentic immune complex glomerulonephritis

leaves lupus nephritis, idiopathic or drug-induced, to be

considered.

Only a few examples of severe nephritis with red

blood cells and red cell casts in the urine have been

described in patients during therapy with hydralazine

[ 11,17,20]. Renal failure seldom has occurred in these

patients [8], and hypocomplementemia has only re-

cently been described [ 171. Another recent report

described hydralazine-induced cutaneous vasculitis without obvious renal manifestations [24].

Figure 1. Glomerulus on left shows minor changes with slight accentuation of mesangium. Glomerulus on right contains a large crescent/c focus of proliferated ceils in Bowman’s capsule that partially replaces the tuft. The remainder of the tuft shows slight mesangial prominence. (Periodic acid-Schiff and hematoxylin stain; original magnification, X 7 15.)



Figure 2. Electron-dense deposits typical of immune complexes can be seen in the electron micrograph of the glomerular mesangium. (&any/ acetate and lead ci- trate stain; original magnification, X 8,200.)

The renal biopsy findings in our patient are consistent

with idiopathic systemic lupus nephritis, but the long

history of therapy with high-dose hydraiazine certainly

raises the question of drug-induced immune complex

disease. Unfortunately, the literature provides no information on how to differentiate the two conditions. We

have not been able to find any reports of renal biopsy

studies in patients with the hydraiazine toxicity syn-

drome.

Several features of our patient’s case are notable.

First, she received hydraiazine for an unusually long

time after the appearance of symptoms that may in

retrospect have represented drug toxicity, and the

symptoms were treated with naproxen rather than with

discontinuation of the hydraiazine. Second, several

features of the biopsy specimen are unusual for severe

idiopathic lupus nephritis: the absence of endotheiiai

and mesangiai proliferative responses, the lack of

abundant subendotheliai immune complexes in electron

micrographs of the giomeruii and the lack of immuno-

reactive IgA in the glomeruiar deposits. Of note, in this

medical center we have seen mesangiai deposits by

electron microscopy in the renal biopsy specimens of

two other patients with presumed hydraiazine-induced

lupus, and neither showed subendothelial deposits. The current patient, however, is the only one of the three in

whom biopsy demonstrated a destructive giomeruiitis. With these considerations in mind, I believe that we very possibly could be seeing a case of hydraiazine-induced

crescentic immune complex giomerulitis. Of course,

the definitive test of this concept would be observation

of the patient’s course after discontinuation of hydral-

azine. in addition, determination of the patient’s N-acetyi

transferase level would be helpful since the hydraiazine toxicity syndrome appears to be confined to slow

acetyiators [8,25]. Dr. Victor Meltzer: I have some follow-up information.

On the ninth hospital day the patient underwent renal

biopsy. Two days later, she began receiving methyi-

prednisoione, 1 g daily for three days. in addition, she

received cyciophosphamide, 100 mg per day,

throughout the remainder of her hospitalization. At the

time of discharge 12 days later, her serum creatinine

level had fallen to 3.6 mg/di. Prior to therapy, her anti-

DNA antibody level was 63 U/ml; on the day prior to

discharge, it was 44 U/ml. Normally, this value does not exceed 15 U/ml; values greater than 25 U/ml occur

largely in patients with lupus. As an out-patient, she

began receiving prednisone, and the cyciophosphamide

was eventually stopped. Six months later, she was readmitted with pneumo-

nia. At that time, still without hydralazine, antinuclear

antibodies were still present, and her serum creatinine level had decreased further to 2.6 mg/dl. Subsequently, she has continued to take alternate-day, low-dose

prednisone; and her most recent serum creatinine level, 12 months after the original hospitalization, was 2.5

mg/di. Without hydraiazine. her blood pressure has



been difficult to control, requiring institution of minoxidil and propranolol. Dr. Atkinson: The elevated level of anti-DNA anti-

bodies provides more evidence in favor of idiopathic

SLE. The gratifying response to therapy does not help

resolve the diagnostic dilemma of idiopathic versus

drug-induced SLE. Since she now is much improved on

low-dose steroids, one could still argue that she had a

drug-induced syndrome. However, I do not believe she

has undergone sufficient follow-up to be certain.

In summary, despite the unusual histologic features

indicated by Dr. Meyer, I still favor the diagnosis of id-

iopathic SLE in this case. However, I would accept the

diagnosis of drug-induced lupus if, over the next two

years, the clinical syndrome and serologic abnormalities

were to remit without further prednisone therapy.

Final pathologic diagnosis: Immune complex cres-

centic glomerulonephritis, possibly hydralazine-in-

duced.

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Renal failure, dyspnea and anemia in a 57 year old woman