Hemolytic-uremic syndrome in a young woman

CLINICOPATHOLOGIC CONFERENCE

Hemolytic-Uremic

Syndrome in a Young Woman

Stenographic reports, edited by Philip E. Cryer, M.D. and John Kissane, M.D., of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals, are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. A 24 year old nurse receiving long-term hemodialysis was admitted to Barnes Hospital for the last time because of fever and flank pain on July 24, 1975. She died one week later. The patient was in apparent good health until January 1973 when she was treated with erythromycin for sore throat and fever. Her blood counts and blood pressure were normal in February. Oral contraceptives, which she had taken since August 1972, were discontinued after March 3, 1973, because of unusually heavy menses, nausea and vomiting. She was hospitalized elsewhere on March 31, 1973, with a one week history of bruising, passage of deep amber urine and facial and peripheral edema. Physical findings included pallor, edema and a blood pressure

of 170190 mm Hg. The hematocrit

cent and the serum urea nitrogen

was 78 mg/lOO

value was 20 per ml. Many red and

white blood cells were noted in the urine sediment. The platelet count was 64,000/mm3, the prothrombin time was 80 per cent of normal, the bleeding demonstrated

time was greater than 30 minutes, hypercellularity

with increased

and the bone marrow numbers

of erythroid

elements and normal megakaryocytes. Blood transfusions were given. The patient was transferred to Barnes Hospital on April 5, 1973. The blood pressure was 170/ 100 mm Hg, the pulse rate 11 O/min, the temperature

36.5OC and the respiratory

rate 24/min.

Respirations

were noted to be labored. The optic discs were flat and no retinal hemorrhages were seen. Positive findings included generalized edema, jugular venous distention to 2 cm above the clavicle at 45 degrees, rales at both lung bases, an audible fourth heart sound and a soft grade l/6 systolic murmur heard best in the fourth intercostal space at the left sternal border. The hemoglobin level was 10.5 g/100 ml, the hematocrit value 30.5 per cent and the white blood cell count 18,700/mm3. Burr cells were noted on the blood smear. Platelet counts ranged from 40,000 to 100,000/mm3 and reticulocyte counts ranged from 20 to 40 per cent. The bleeding time was consistently greater than 20 minutes. The serum bilirubin was 1.8 mg/ 100 ml and the lactic dehydrogenase (LDH)

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was 800 mlU/ml. Coombs’ tests were only weakly positive on two occasions. Lupus erythematosus preparations were negative as were tests for antinuclear antibodies. Two to three red blood cell casts were seen

eruption over the lower extremities showed perivascular infiltration with inflammatory cells. A purified protein

in each high power

prednisone

was 2-t proteinuria. mg/lOO

field in the urine sediment. The serum

creatinine

ml and the uric acid 17.4 mg/lOO

An arteriovenous

shunt was inserted

There

was

11.2

ml.

derivative skin test was negative. Therapy with isoniazid, ethambutol and cyclophosphamide was begun; blindness

therapy prompted

demonstrated

and hemodial-

was

continued.

An episode

an electroencephalogram,

delta wave activity

region, and a lumbar puncture.

of

which

in the left temporal

No abnormalities

of the

ysis was begun. An arteriovenous fistula was subsequently constructed. A single episode of hemoptysis occurred on April 15. Pulmonary infiltrates were noted

cerebrospinal fluid were detected, and brain scans were again within normal limits. The patient was discharged to receive hemodialysis in a satellite unit. Redness and

on chest

tenderness

roentgenograms

at that time.

Therapy

with

of the arteriovenous

fistula

were

noted

prednisone, 80 mg daily, was followed’by an increase in the platelet count from 27,000/mm3 to 230,000/mm3

during outpatient visits. Pain in the right side of the chest and in the flank, and

and a decrease

nausea, beginning on July 18 led to her readmission to Barnes Hospital on July 24, 1975. The blood pressure

in the serum LDH to 520 mlU/ml;

the

bleeding time remained greater than 20 minutes. The prothrombin time was 48 per cent, the partial thromboplastin

time 25 seconds and the fibrinogen

mg/lOO

ml. The half time of disappearance

mium-labeled red blood cells was nine An open renal biopsy was performed the specimen obtained demonstrated swelling and proliferation, with modest

level 295 of 51chro-

days. on April 18 and marked intimal intimal fibrosis,

was 160/100

mm Hg, the pulse rate 120/min,

the res-

piratory rate 24/min and the temperature 39.2’C. New findings included a coarse rub at the base of the right lung and right costovertebral

angle tenderness.

There

of medium and small arteries associated with tubular atrophy. Deposits of immunoglobulin G (IgG) and M (IgM)

was no cutaneous evidence of emboli. Blood cultures were obtained and gentamicin was administered. Staphylococcus aureus was recovered from all blood cultures, and therapy with oxacillin was added. One and a half hours after a 2.0 g intravenous dose of oxacillin

in the arterial walls were also demonstrated. Serum total hemolytic complement levels were 125 units (normal

a generalized seizure occurred. Computerized axial tomography of the brain was normal as were findings

150 to 250 units); the level of C’3 was 65 mg/lOO

on lumbar puncture. Skin tests with oxacillin, penicillin G, penicilloyl polylysine and penicilloic acid were

(normal

ml

101 to 189 mg/ 100 ml) and the level of C’4 was

36 mg/ 100 ml (normal 20 to 40 mg/lOO ml). Because of hypertension, the patient was treated with methyldopa

and hydralazine.

was heard, and progressive silhouette peratures

A pericardial enlargement

was documented. A hectic as high as 40°C, developed

friction

rub

of the cardiac fever, with temduring hospital-

ization; the temperature subsequently returned to normal. Liver-spleen scans and brains scans were within normal

limits.

The patient

was discharged

to receive

hemodialysis

as an outpatient, but she was readmitted to Barnes Hospital on June 10, 1973, because of fever and dyspnea. The temperature was 38OC and rose to 41.2OC over the next two days. Additional findings included venous engorgement of fundic vessels, a linear hemorrhage adjacent to the right optic disc, a grade 2/6 systolic murmur along the left sternal border, a right ventricular lift, a summation gallop and an accentuated pulmonic component of the second heart sound. There was no growth on six cultures of the blood. Interstitial infiltrates were noted on chest films and a pericardial effusion was documented angiographically. Pericardiectomy and lung biopsy were performed on June 25. Chronic inflammation and a few granulomas were seen in the pericardial specimens; stains for acid-fast bacilli were negative. Biopsy of a pruritic, maculopapular

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negative.

On July 29, following

a second generalized

another dose of oxacillin,

seizure, which began in the upper

right arm, occurred and was followed by a cardiac arrest. Cardiac resuscitation was successful, but artificial ventilating

was required

thereafter.

It was suspected

that the patient had aspirated. Sputum cultures grew Pseudomonas aeruginosa repeatedly but, despite this, vancomycin and chloramphenicol were given to treat the staphylococcal bacteremia and “anaerobic” aspiration pneumonia. Absent electroencephalographic activity was documented on three successive days following the cardiac and respiratory arrest. Bradycardia preceded the patient’s death on the following day. CLINICAL

DISCUSSION

Dr. Gerald Medoff:

This is a long and complicated case history. I do not think that it will be productive or possible to cover every detail in the protocol or to present an explanation for every clinical finding. I would like to view the x-ray films before starting our discussion. Dr. Gilbert Jost: In April 1975 the heart was enlarged, a finding consistent with chronic renal failure. The cardiac silhouette also had a configuration that was characteristic of a previous pericardiectomy. At the time of her cardiopulmonary arrest in July, the chest film demonstrated congestive heart failure. There was also

Volume 60

HEMOLYTIC-UREMIC

an early infiltrate

in the upper lobe of the right lung. On

interval

resolution

of the infiltrate

trates scattered of borderline Dr. Medoff:

were

lytic-uremic diagnoses membrane

throughout

nonspecific

monary

congestive heart failure. Thank you. I would like to divide the dis-

of the first admission

results

of the would

kidney

separating

you run through

them.

the differential

illness.

Either

[4]

rapidly

progressive

or mesangiocapillary

may present

with the hemo-

syndrome; no evidence regarding these is available. Antiglomerular basement induced glomerulonephritis with Good-

infiltrates

two weeks agnosis

into two parts, with the

biopsy

her

glomerulonephritis

IN A YOUNG WOMAN

pasture’s syndrome may be associated with the features of the hemolytic-uremic syndrome. In this patient pul-

infil-

the right lung and evidence

cussion Hoffsten,

in the upper lobe of

some

for

glomerulonephritis

suggested an aspiration pneumonia. The final chest film, taken shortly before the patient’s death, revealed some the right lung, but there

etiology crescentic

the following day the infiltrate was more prominent, and the sequence of events and roentgenographic findings

SYNDROME

or hemoptysis

after she was anuric;

of Goodpasture’s

did not develop

until

for this reason,

a di-

syndrome

is unlikely.

Poly-

arteritis nodosa or systemic lupus erythematosus are diagnoses to consider in this patient but neither seems likely.

Dr. diag-

nosis of this patient’s kidney disease at the time of her first admission to Barnes Hospital in 1973? Tell us the

Complications of pregnancy may be associated the features of the hemolytic-uremic syndrome.

diagnosis you favor, and comment on her therapy during that admission. Dr. Philip Hoffsten: The renal aspect of this patient’s

with This

patient was not pregnant and there was no history of a recent pregnancy. Several recent reports of acute renal failure

illness was apparently quite acute and progressed from normal function to total, permanent renal failure in two

associated

with the use of oral contraceptives

In the last week of March 1973, she noted easy

[5-7] may be pertinent in this case. The evidence is compelling regarding the ability of oral contraceptives

bruising, nausea and edema which were progressive. When admitted to her local hospital on March 31 she

to increase the blood pressure [8] and to alter parameters of coagulation [9]. This patient had been using

had a hematocrit value creatinine of 10 mg/lOO

oral contraceptives of her illness.

weeks.

of 20 per cent and a serum ml. By April 6 she was anuric.

for nine months

prior to the onset

She required support by an artificial kidney for the remaining two years of her life. Her platelet count was 64,000/mm3 on admission to her local hospital and

Other causes of this patient’s acute renal failure should be considered. Acute, reversible intrinsic renal failure (acute tubular necrosis) is not favored because

remained

her urine sediment contained red blood cell casts. Her urine sodium concentration was 21 meq/liter, a value

depressed

for several

weeks

after

she be-

came anuric. Early in her hospitalization she did not have detectable serum antinuclear antibodies or antibodies to streptococcal antigens. Her blood pressure level was elevated although not to levels a patient with malignant hypertension. This patient had the hemolytic-uremic acute renal failure, thrombocytopenia

expected

lower

in

syndrome of and microan-

children,

the hemolytic-uremic

etiologic patterns

agents and has in the kidney. In

syndrome

is most often

a self-limited form of acute renal failure suspected to be related to acute viral infection. Supportive therapy with an artificial kidney may be necessary in severe cases, but neither heparin nor corticosteroid therapy have a clear beneficial effect. In children, recovery is usually complete without residual renal impairment [ 21, although one series reports residual renal impairment in half of the children studied [3]. In adults, the prognosis is grave and recovery is unusual. The syndrome may be associated with acute glomerulonephritis secondary to streptococci or other agents; this patient was exposed to scarlet fever although there was no subsequent serologic evidence indicating that she incurred a streptococcal infection: I do not favor this

in acute tubular

of an inciting

agent

necrosis.

There

for acute

tubular

necrosis and this diagnosis need not be considered further. Bilateral cortical necrosis is one of the pathologic diagnoses associated with the hemolytic-uremic syndrome. The lactic tration in this patient’s

giopathic hemolytic anemia as first described by Gasser and co-workers [ 1] The clinical syndrome is associated with a variety of presumed several possible histologic

than expected

was no history

dehydrogenase (LDH) concenserum was approximately 800

mlU/ml on several determinations while her renal failure was progressing. This amount of LDH is compatible with her severe hemolytic anemia but is lower than expected if she were to have infarcted both kidneys. Lastly, one should always

consider

obstruction

of the urinary tract

as a cause of acute renal failure. Her clinical history does not favor that diagnosis. The clinical diagnosis in this patient would be hemolytic-uremic syndrome. Based on the presence of red blood cell casts in her urine, remarkable

glomerular

pathology, probably with fibrin deposition, would be expected. The etiology of her disease is not obvious. Dr. Medoff: I just want to re-emphasize a point you made. When you call her disease hemolytic-uremic syndrome, you are truly calling it a syndrome and not a disease. In other words, it may have multiple etiologies and more than likely represents multiple entities. Dr. Hoffsten: This is correct. One other point should

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be stressed with respect to her therapy. If any intervention with drugs was anticipated, it should have been started on the day of admission. What would you have done to treat her? Dr. Medoff: This is controversial and data on which Dr. Hoffsten: to base a decision istration

of heparin

are scant. I would favor the adminand an antiplatelet

se, and one does not need to implicate an autoimmune mechanism. Although renal failure may be the presenting manifestation of systemic lupus erythematosus, this type of presentation

drug, such as

I am confident

dipyramidol, started on the day of admission and prior to a renal biopsy. If a renal biopsy is performed first,

Polyarteritis

adequate anticoagulation frequently leads to severe hemorrhage at the biopsy site necessitating cessation of anticoagulant therapy or even surgical intervention. The prognosis of the hemolytic-uremic syndrome in an adult is so grave that I would favor a trial of therapy without a biopsy proved diagnosis. Dr. Atkinson, two other diagnoses menDr. Medoff: tioned in the chart and also mentioned by Dr. Hoffsten were polyarteritis

and systemic

lupus erythematosus.

Can you comment on both of these and any others that you think might be appropriate? I do not believe either diagnosis is Dr. John Atkinson: likely.

Most,

if not all,

of the presenting

signs

and

symptoms and abnormalities on physical examination and laboratory evaluation can be ascribed to renal failure and its complications. The major exception is the hemolytic anemia. The presence of microangiopathic anemia favors the diagnosis of the hemolytic-uremic syndrome rather than a collagen-vascular disorder, although this type of hemolytic anemia is occasionally seen in fulminant connective tissue diseases. Nevertheless, the two entities mentioned by Dr. Medoff, as well

as Wegener’s

granulomatosis,

Goodpasture’s

must be quite rare. In fact, I

was unable to find a report of a patient presenting like this in whom a positive serology developed later. Thus, in ruling out this possibility. nodosa

is a more attractive

diagnosis.

This patient had a hectic and largely unexplained febrile clinical course, eosinophilia, skin rash, pulmonary infiltrates findings

and acute renal failure. This constellation of certainly does suggest a systemic vasculitis,

particularly the allergic or granulomatous variety of angititis in which pulmonary involvement is common. Except for birth control pills, the patient was not taking any drugs suspected to be of etiologic importance in allergic angiitis. There are a few reports of an apparent systemic vasculitic-like illnesses developing in association with the use of birth control pills. After reviewing these rare cases, I was not convinced that the birth control pills played an etiologic role. From the information available I am not able to exclude a systemic arteritis. The correct diagnosis in this case obviously rested upon obtaining additional biopsy material for pathologic examination and/or roentgenographic evaluation of the renal vessels. Dr. Medoff: What about the serum complement values? Dr. Atkinson:

We now know that there are two major

pathways of complement activation. The classic pathway is activated by antibody and proceeds through the sequential activation of C’l, C’4 and C’2 to the ac-

syndrome and scleroderma need to be considered in the differential diagnosis in a patient presenting with a

tivation of C’3 and the later components of the complement sequence. The alternate, or properdin, pathway

systemic illness and unexplained can dispense with Wegener’s

is activated by antibody under certain circumstances but also by complex polysaccharides and lipo-polysaccharides as are found in some bacterial and fungal cell walls. It bypasses C’l, C’4 and C’2 and proceeds

acute renal failure. We granulomatosis and

Goodpasture’s syndrome because of the lack of prominent upper and/or lower respiratory tract symptoms. Likewise, although there are rare reports of patients with scleroderma presenting with a paucity of peripheral findings and acute renal failure, in this case there were no skin, vascular or gastrointestinal manifestations of scleroderma. With respect to systemic lupus erythematosus, this patient had a host of negative findings including the lack of arthralgias or arthritis, typical rash, sun sensitivity, oral ulcers, alopecia and so forth. However, and more importantly in this case, serologic studies for systemic lupus erythematosus were repeatedly negative. Moreover, the hemolytic anemia was Coombs’ negative and apparently on a microangiopathic basis whereas in systemic lupus erythematosus it is usually a Coombs’ positive IgG-mediated autoimmune process. The decreased platelet count may have been secondary to the presumed hemolytic-uremic syndrome or uremia per

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to the activation of C’3 through a series of proteins which are as yet not as well defined as those of the classic pathway. Immune complexes can activate either pathway. For example, in systemic lupus erythematosus in which there are circulating DNA-anti-DNA complexes, depressed serum levels of C’4 and C’2 as well as C’3 are commonly found indicating classic pathway activation. However, the alternate pathway may also be activated in some patients with systemic lupus erythematosus as evidenced by low concentrations and increased turnover rates of alternate complement proteins (properdin, factor B) as well as depressed C’3 but normal C’4 concentrations. In addition, by immunofluorescent technics the alternate pathway proteins have been found to be deposited in the glomeruli of systemic lupus erythematosus kidneys. In acute poststreptococcal, and in some forms of chronic membra-

Volume 60

HFMOLYTIC-UREMIC

neous,

glomerulonephritis

primarily

engaged.

molytic-uremic

the alternate

In the very

syndrome

pathway

few patients

in whom

is

with he-

complement

com-

either

by immune

or by another

as yet un-

festations

were most likely related to thrombocytopenia

mal) and components

hemolytic-uremic

of the alternate

pathway

sistent

(which

general

Dr. Medoff: a microangiopathic hemolytic anemia? Do we have any evidence of disseminated intravascular coagulation in does the hemato-

logic picture most favor? Dr. J. Heinz Joist: This patient undoubtedly had an acute, severe hemolytic anemia. The Coombs test was negative, poikilocytes and burr cells were seen on a peripheral blood smear at the time of admission to the consultant at Barnes more commonly re-

or fragmented

red blood cells.

microangiopathic hemolytic anemia, must be entertained. Red blood cell fragmentation is typically seen in patients with the hemolytic-uremic syndrome and purpura, a closely

circulation

transient

to uremia

[ 141 indicating

localized

(kidneys) with predominant However, it is possible that

so as to produce

DIC [3,15],

the picture

which would escape

of

detection

in

patients studied several days after the acute onset of the disorder. There may also be differences between the laboratory

findings in children

and in adults with the

hemolytic-uremic syndrome. Dr. Medoff: Would you have favored the use of heparin in this patient? Dr. Joist: Yes, I would favor the use of heparin in patients with the hemolytic-uremic syndrome in the acute phase of the disorder regardless of the severity of the hemostatic abnormalities found, i.e., even sence of DIC. I say this because I believe deposition

Although we do not have data for plasma hemoglobin or haptoglobin, which would have been helpful, the diagnosis of intravascular hemolysis or, more specifically,

thrombocytopenic

syndrome coagulation of platelets.

related

data would seem confound in patients with the

the associated intravascular process in some patients, particularly in the acute phase, may spill over into the

levels. Thank you very much. Dr. Joist, was this

outside hospital, and a hematology Hospital noted “smashed cells”

dysfunction

with those generally

intravascular sequestration

by the presence of renal failure and hemolytic anemia and the use of corticosteroids. All these may influence

and what renal disease

platelet

[ 12,131. Thus, the laboratory

should be reduced). Serial determinations also might have been helpful. I would favor this general interpretation of the complement data, but it must be tempered

thrombotic

test

fibrin degradation product level was only minimally elevated (6.4 yglml). The mild clinical bleeding mani-

complexes

ferred to as schistocytes

sulfate precipitation

for these findings is that alwas occurring in this patient

and, perhaps,

this patient

protamine

i.e., low

VIII, V, II and fibrin-

ml) and the thrombin time (19.1, 14.5 set) were normal on two occasions, the PSP was negative and the serum

the C’4 level

known mechanism. Confirmation of this hypothesis could be obtained by measuring additional early components of the classic pathway (which should be nor-

complement

coagulopathy, factors

was

low whereas

normal. One explanation ternate pathway activation

IN A YOUNG WOMAN

(PSP) indicating circulating high molecular weight fibrinogen complexes. In this patient, the prothrombin time (10.0, 13.5 set), fibrinogen level (370, 295 mg/lOO

With this introduction what can one say about this patient’s complement levels? The whole complement were

of a consumption

levels of the labile clotting ogen, and a positive

ponents have been measured, they have usually been modestly increased or normal.

and C’3 levels

onstration

SYNDROME

in the

glomerular

in the abthat fibrin

capillaries,

although

probably a secondary event, i.e., a response to vascular injury, is likely to be a major contributing factor to the deterioration of renal function and may determine the extent of permanent renal damage. As Dr. Hoffsten has already therapy

pointed out, one of the reasons why heparin has apparently failed to influence the course

of the disorder in many published reports is, perhaps, the fact that it was given too late. In addition, since platelet consumption is a consistent and frequently

related

disorder. However, it has also been observed in patients with other conditions such as malignant hypertension, eclampsia, acute poststreptococcal glomerulonephrids and prosthetic cardiac valves.

predominant finding in patients with the hemolyticuremic syndrome, I would favor the administration of

There is strong evidence [IO] that this sometimes bizarre red blood cell fragmentation is due to intravas-

antiplatelet drugs such as a combination of aspirin and dipyramidole [ 161 or sulfinpyrazone as a single agent

cular coagulation, i.e., the shearing of red cells during their passage through fibrin thrombi in the microcirculation. In patients with microangiopathic hemolytic

in addition to heparin therapy as early as possible. Although such a combined anticoagulant/antiplatelet drug regimen potentially carries an increased risk of bleeding

anemia, the platelet count is almost always reduced, fibrin degradation products in serum are frequently increased and fibrinogen catabolism is increased [ 111. However, only rarely is there clear evidence of disseminated intravascular coagulation (DIC), if that term is used in a more restricted sense requiring the dem-

complications, the generally poor prognosis patients with the hemolytic-uremic syndrome this additional risk, in my view. Thrombolytic has been used in recent studies [ 17,181, but it readily available and its usefulness in this cannot be sufficiently assessed at present.

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Figure 1. Photomicrograph of renal biopsy specimen showing marked subendothelial intimal thickening by myxoid connective tissue (right). Toluidine blue stained epoxyembedded section: original magnification X 320, reduced by 15 per cent.

Figure 2. Photomicrograph of renal biopsy specimen showing glomerular stiffening, tubular atrophy and interstitial fibrosis. tiematoxylin and eosin stain: original magnification X 360, reduced by 75 per cent.

Dr. Medoff:

you are making an anatomic diagnosis, phrosclerosis, which also has multiple

I think I am correct

the diagnosis patient,

of hemolytic-uremic

in saying we all favor syndrome in this

and we all agree that in making

this diagnosis

we have said nothing about the pathogenesis or etiology of this syndrome. Our consultants are also in agreement that a trial of heparin should have been given early, and if the patient biopsy

failed to respond

to the heparin,

should have been performed.

A kidney

a kidney biopsy

was performed without the preceding heparin trial and I would like Dr. Kissane to go over the biopsy with us and tell us his anatomic diagnosis.

Dr. John Kissane: specimen

The abnormalities in this biopsy essentially of a proliferative oc-

consisted

clusive process involving small muscular arteries and arterioles, and the parenchymatous consequences of relatively abrupt ischemia. The vascular lesion consisted of very marked deposition of loose myxoid subendothelial

connective

tissue (Figure

1).

of which is the hemolytic-uremic complete agreement between pathologist in that the clinical uremic syndrome can explain

malignant etiologies

neone

syndrome. So we have the clinicians and the diagnosis of hemolyticthe clinical findings and

the histologic changes. Neither the clinical diagnosis nor the anatomic diagnosis, however, says anything about the etiology of this patient’s disease. Dr. Hoffsten has alluded to the fact that this syndrome of microangiopathic hemolytic anemia and renal failure has been reported mainly in infants and young children [20]. However, it has also been described in adults [21]. The etiology of the syndrome is unknown, but autoimmune mechanisms and viral and other infections have been implicated. In addition, a significant proportion of cases in adults occur in women lately postpartum [ 191. Recently, there have been several reports

were necrotic, others were sclerotic, tubules were markedly atrophic and dilated and the interstitium was increased in amount (Figure 2). The changes are iden-

of malignant nephrosclerosis as part of the hemolyticuremic syndrome in women taking birth control pills [6,7]. Because this patient’s illness occurred while she was taking birth control pills, and the clinical story and pathology are similar to those in the reported cases, I will hypothesize that the initiating event in this case was

tical with those described as “postpartum nephrosclerosis” by Robson and others [ 191 of which about 30 examples have been described in the literature. In a much smaller number of cases, the lesions have been associated not with recent pregnancy, but, as in our case, with birth control pills. The pathogenesis remains unknown. Dr. Medoff: Thank you. Our clinicians are making a diagnosis of a syndrome, the adult form of the hemolytic-uremic syndrome which has multiple etiologies;

the !‘pill.” Having made that diagnosis, I am impressed enough with the reports in the literature of responses of this syndrome to heparin therapy [22-271 that I believe such treatment might have been beneficial and should have been used. I would like to cover, briefly, the clinical problems encountered in her subsequent admissions. I have no explanation for her episode of pericarditis, except to say that the most likely explanation was her uremic

In some vessels the lesions were unquestionably thrombi in varying stages of organization. The vascular media was normal. In the parenchyma some glomeruli

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HEMOLYTIC-UREMIC

state. I suspect that the granulomas were not secondary

to tuberculosis,

who has this organism

in the pericardium but I certainly

with the institution of antituberculous

therapy,

pharynx

agree

to her primary

disease

and may have been secondary

to a drug reaction. Her final admission was precipitated by an episode of sepsis. Her outpatient records reveal that she had had repetitive problems with infections in her fistula. The site of her fistula was described as red and tender on admission, and I think it is reasonable to assume that this was the source of her staphylococcal bacteremia. Recurrent

staphylococcal

infections

in the fistula

or

cannula of hemodialysis patients is a common problem and represents a source of bacteremia [ 281. Wilson and Hamburger (291 have emphasized that the possibility of endocarditis must be strongly suspected in all instances of proved staphylococcal bacteremia; the diminished resistance to infection in the uremic state must also

be considered

an important

contributory

be important

in explaining

factor

this complication

in the posterior

I believe

that the origin of this patient’s

renal disease was the hemolytic-uremic syndrome resulting from birth control pills. The pathology, however, two years after the acute disease, will very likely show end-stage renal disease, and no etiology will be diagnosable. She will very likely have left-sided, and possibly right-sided, bacterial endocarditis although it is possible

that after two weeks

of therapy

the endocar-

ditis could have resolved. It is also probable that there will be abscesses in various organs, specifically the central nervous system. If her arteriovenous fistula is examined, there will be evidence of infection at that site. Because of the aspiration and prolonged apnea, there will be changes of hypoxia in the brain. She will have a severe bronchopneumonia secondary to Pseudomonas

and there

may also be superinfection

with a

fungus. PATHOLOGIC DISCUSSION Dr. Charles

Kuhn:

The

kidneys

at autopsy

were

markedly contracted and showed very few specific changes. Tubules were severely atrophied, glomeruli hyalinized and the arteries markedly thickened: the

[30,31]. In addition, the demonstration that circulatory stress induced by large arteriovenous fistulas in dogs frequently resulted in bacterial endocarditis [32] may also

in residence

[36].

In summary,

especially

in light of the fact that she was a nurse, and had a history of positive tuberculin skin test in the past. I likewise have no explanation for the finding of vasculitis in the skin biopsy specimen. I believe that this was unrelated

SYNDROME IN A YOUNG WOMAN

lumen was narrowed

in

patients without preexisting valvular heart disease. Therefore, the probability that this patient had endo-

intralobar

arteries

with septic pulmonary embolization. The two seizures she had could have been secondary to embolization from an infected valve on the left side

(Figure

3). In con-

was collagenized.

The skin biopsy

carditis is very high. The fact that her disease started with right-sided chest pain and the presence of pneumonia raises the question of right-sided endocarditis

or obliterated

trast to the biopsy specimen which had an active acute myxoid intimal thickening, at autopsy the intima of the specimen

had very little to tell us

about the primary disease. There were a few perivascular inflammatory cells which would be compatible with drug reaction. There was no unequivocal evidence that the primary

disease did extend outside the kidney.

esting that both seizures occurred after a dose of oxacillin. Seizures have been reported after penicillin ad-

In the capsule of the adrenal there were several arteries which were thickened with hyalinized media (Figure 4). Although abnormal, the changes were consistent with her hypertension.

ministration [33], but this complication is usually related to exorbitant dosages of the drug. Under usual circumstances, 2 g of oxacillin should not cause seizures,

phases of the disease, the lung biopsy specimen, did show thrombi in small arteries. The difficulty

of her heart or to multiple

but we have seen similar

brain abscesses.

complications

It is inter-

We did have one other source of tissue from the early

of other drugs

in patients with compromised renal function [34]. This may be secondary to an enhanced transport of drugs into the central nervous system of patients with uremia

[351. The last few days of the patient’s life are not described in detail in the protocol, but I think a few comments are necessary. The patient aspirated after her last seizure and, on the basis of the diagnosis of aspiration pneumonia, she was treated with chloramphenicol. The antibiotic was used despite multiple sputum cultures which grew Pseudomonas aeruginosa. I think that it is important to realize that Pseudomonas may cause aspiration pneumonia in the debilitated patient

which is that

by the time the biopsy was performed, the shunt had been placed and dialysis had started. The thrombi were few and scattered, and it is difficult to know whether they were manifestations of the primary disease or small emboli from the shunt. The other changes in the lung biopsy specimen, those which were widespread enough to be responsible for the roentgenographic changes, were a mixture of hemorrhage into the air spaces, fibrin exudate and alveolar septai thickening (Figure 5) explained by a combination of uremia and bleeding tendency. Uremic pneumonitis has a hemorrhagic component and because of her abnormal hemostasis, the hemorrhagic component was exaggerated.

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CLINICOPATHOLOGIC CONFERENCE

Figure 4. A small artery with a severely hyalinized media just beneath the capsule of the adrenal gland. Hematoxylin and eosin stain; original magnification X 250, reduced by 17 per cent.

Figure 3. The kidney at autopsy. A small muscular artery is obliterated by fibrous tissue. The renal tubules are atrophic and glomerulus hyalinized. Masson’s trichrome stain; original magnification

X

100, reduced by 17 per cent.

molysis,

There were three microscopic noncaseous granulomas in the biopsy specimen. There were no organisms, and I agree with Dr. Medoff that the granulomas are a red herring and that the disease in the pericardium

generally related to plugged bronchi. Evidence of hemolysis was present The spleen

showed

extensive

topoiesis. There was hemosiderin which is an anatomic hallmark

in many organs.

extramedullary

hema-

in the renal tubules, of intravascular he-

Hemosiderin-laden macrophages in the lung are Figure 5. evidence of earlier hemorrhage. Hematoxylin and eosin stain: original magnification X 250, reduced by 17 per cent.

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was marked

hemosiderosis

in the

the cortical grey matter of the entire cortex, the basal ganglia and cerebellum (Figure 6). The age of these lesions was about two weeks, certainly consistent with

and lung was probably uremic. At autopsy, the lungs were very edematous, there was still some residual fibrosis left over from the acute phase and there were still many old thrombi. In addition, there was mucus blocking of many of the airways, and patchy bronchopneumonia

and there

spleen, lymph nodes, lungs and liver. In the central nervous system we found severe hypoxic encephalopathy with massive necrosis involving

the history of having started at the time of her seizure. We found no other etiology for the seizure. We were unable to find any bacterial endocarditis either active or healed and presume that the septicemia was all relalted to her fistula. The final anatomic diagnoses were history of hemolytic-uremic

syndrome

(S.P. 73-4275);

bilateral

renal

The hippocampus. A broad layer of resorbing Figure 6. necrosis with focal hemorrhages occupies the deep zones of the cortex. Hematoxylin andeosin stain; original magnification X 20. reduced by 17 per cent.

60

HEMOLYTIC-UREMICSYNDROME IN A YOUNG

scarring, ease:

severe,

fibrous

multiple;

consistent

pericarditis;

arteriolosclerosis

with end-stage

in the

lung,

tramedullary hematopoiesis rotizing tracheobronchitis;

of the adrenal capsule:

focal

monary edema:

microemboli

renal dis-

interstitial fibrosis of the myocardium; hypertrophy of the heart, 650 g (history of hypertension): hemosiderosis of the liver, spleen, lymph nodes, lung and kidney; ex-

massive

in the spleen; acute necbronchopneumonia; pulhypoxic

encephalopathy.

Editors’ note: The patient discussed in this conference reported on elsewhere

WOMAN

has been

[37].

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versible post partum renal failure. A new syndrome. 0 J Med 37: 423, 1968. Kaplan BS, Katz J, Krawitz F, et al.: An analysis of the results of therapy in 67 cases of the hemolytic-uremic syndrome. J Pediatr 78: 420, 197 1. Clarkson AR, Lawrence JR, Meadows R, et al.: The haemolytic uremic syndrome in adults. Q J Med 39: 227, 1970. Luke RG, Talbert W, Siegel RR, Holland H: Heparin treatment for postpartum renal failure with microangiopathic haemolytic anemia. Lancet 2: 750, 1970. Luke RG: Postpartum renal failure. Arch Intern Med 129: 835, 1972. Ponticelli C, lmbasciati E, Tarantino A, Graziani G: Postpartum renal failure with microangiopathic haemolytic anemia. Lancef 2: 1034, 1970. Ponticelli C, lmbasciati E, Tarantino A, Graziani G, Redaelli G: Postpartum renal failure with microangiopathic haemolytic anemia: long-term survival after anticoagulant therapy. Nephron 9: 27, 1972. Benson L, Cuppage RE, Grantham J: Disseminated intravascular coagulation: Postpartum hemolytic-uremic syndrome with recovery of renal function. J Kansas Med Sot 72: 138, 1971. Donadio JV, Holley KE: Postpartum acute renal failure: Recovery after heparin therapy. Am J Dbstet Gynecol 118: 510,1974. Pendras JP, Smith MJ: The silastic-Teflon arteriovenous connula. Trans Am Sot Artif Intern Organs 12: 222, 1966. Wilson R, Hamburger M: Fifteen years’ experience with staphylococcus septicemia in a large city hospital. Analysis of fifty-five cases in the Cincinnati General Hospital 1940 to 1954. Am J Med 22: 437, 1957. Schreiner GE, Maker JF: Uremia. Springfield, Ill., Carles C Thomas, 196 1, p 363. Montgomerie JZ. Kalmanson GM, Guze LB: Renal failure and infection. Medicine 47: 1, 1968. Lillehei CW, Bobb, JRR, Vischer MB: The occurrence of endocarditis with valvular deformity in dogs with arteriovenous fistulas. Ann Surg 132: 577, 1950. Fossieck B Jr, Parker RH: Neurotoxicity during intravenous infusion of penicillin. J C/in Pharmacol 14: 504, 1974. CPC. Generalized seizures following isoniazid therapy for tuberculosis in a patient with uremia. Am J Med 53: 765, 1972. Raskin NH, Fishman RA: Neurologic disorders in renal failure. N Engl J Med 294: 143, 1976. Tinstman TC, Dines DE, Arms RA: Postoperative aspiration pneumonia. Surg C/in North Am 53: 859, 1973. Schoolwerth AC, Sandler RS, Klahr S, Kissane JM: Postpartum nephrosclerosis and nephrosclerosis in women taking oral contraceptives. Arch Intern Med 136: 178, 1976.

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