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CASE 8 FOCAL GLOMERULAR LESIONS IN FUNGAL ENDOCARDITIS
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Case 8 Focal Glomerular Lesions in Fungal Endocarditis
William C. Roberts, M.D., and Alan S. Rabson, M.D.
Bethesda, Maryland
FOCAL AREAS of necrosis and sclerosis have frequently been seen in the renal
glomeruli of autopsied patients with subacute endocarditis due to bacteria. These
glomerular le sions have been called “focal embolic (endocarditic) glomerulonephriti s,”
with the implication that they were the result of multiple small emboli, which
were dislodged from cardiac vegetations and landed in the glomerular capillaries.
1
summarized the reasons for rejecting the embolic theory of the pathogenesis
Allen
of these lesions and agreed with Longcope
an allergic nature. Since fungal infections in man are commonly associated with
manifestations of hypersensitivity to the organisms, the presence of focal glomerular
lesions in some patients with endocarditis caused by fungi might be expected. Focal
glomerular lesions have been mentioned in four
of endocarditis caused by the higher fungi (Eumycetes) reported in the literature,
and all four have been in patients with endocarditis caused by organisms of the
Candida species. Nine
3,8
of these 44 patients with fungal endocarditis were studied
clinically and at autopsy at the Clinical Center of the National Institutes of Health, and
one of the nine showed the typical renal lesion of “focal embolic glomerulonephritis.”
The latter patient is the subject of this communication.
2
who considered these lesions to be of
3–6
of the 44 autopsy-proven cases
3, 7, 8
CASE REPORT
A 26-year-old Puerto Rican man (C.C. No. 02–78–74), who was a narcotic addict,
was transferred to the Clinical Center (National Institute of Allergy and Infectious
Diseases) from a federal penitentiary hospital two months prior to death. He gave
no history of rheumatic heart disease. He was in good health until 11 months
before death, when he experienced acute left upper quadrant abdominal pain,
and was believed to have a splenic infarct. Shortly after this episode he had the
onset of fever which persisted until his death. Aheart murmur and splenomegaly
also were noted, and three blood cultures were positive for Candida parapsilosis.
Hemolytic Staphylococcus aureus, coagulase negative, grew in one of the blood
cultures. The patient was treated with penicillin, streptomycin, and neoantimosan
(Fuadin) without clinical response. Five months before death, anemia and
thrombocytopenia were noted. His urine showed hematuria, pyuria, albuminuria,
and cylindruria.
On admission to the Clinical Center, his temperature was 38.6°C; heart
rate, 132/min; respiratory rate, 30/min; and blood pressure, 100/60mm Hg.
He was chronically ill, thin, and pale. Petechiae were present in the lower
conjunctival sac and over the right buttock. The heart was not enlarged. Aloud,
Received August14, 1961; accepted for publication November22, 1961.
From the Pathologic Anatomy Department, Clinical Center, National Institutes of Health,
Bethesda, Maryland.
Requests for reprints should be addressed to William C. Roberts, M.D., Pathologic Anatomy
Department, Clinical Center, National Institutes of Health, Bethesda 14, Maryland.
DOI: 10.1201/9781003409281-1 1
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high-pitched, blowing systolic murmur was heard over the precordium. The
liver and spleen were markedly enlarged and tender. There was clubbing of the
fingers bilaterally.
During the hospital course, the hemoglobin ranged from 6.9 to 8.9 g/100 ml;
platelet count, from 44,000 to 120,000/mm
3
. The leukocyte differential count showed more than 50% lymphocytes on all
mm
3
; and leukocyte count, from 2,400 to 4,300/
determinations. The erythrocyte sedimentation rate (Westergren method) was 104 to
140mm/hr; blood urea nitrogen was 36 to 63 mg/100 ml; uric add, 6.7 to 9 mg/100 ml;
creatinine, 2.6 to 3.5 mg/100 ml; calcium, 8.4 to 9.2 mg/100 ml; alkaline phosphatase,
20 to 53 King-Armstrong units; albumin, 1.6 to 2.1, and globulin, 5.5 to 6.5 g/100
ml; bromsulphalein retention in the blood, 6 to 16% at 45 min; cephalin occulation
test, 3 to 4+; and thymol turbidity, 13 to 20 units. Multiple urinalyses revealed
the presence of innumerable erythrocytes and leukocytes with persistent 1 to 3+
albumin, and “occasional” to a “moderate number” of granular casts. Serial Addis
counts disclosed persistently abnormal values for erythrocytes, leukocytes, and
casts. Nine urine cultures were positive for Klebsiella and hemolytic Staphylococcus
albus, coagulase negative, hemolytic Staphylococcus aureus, coagulase positive, or
both, but colony counts were less than 50,000 bacteria/ml of urine, except once
when the count was greater than 1million/ml of urine. The phenolsulfonphthalein
test showed 12% excretion at the end of two hours, and the Fishberg concentration
test showed maximal concentration to be only 1.010. Thirty-one blood cultures and
one bone marrow culture were positive for Candida parapsilosis. None of the blood
cultures were positive for bacteria.
Two days after admission to the Clinical Center, the patient had clinical and
electrocardiographic evidence of a massive anterior wall myocardial infarct. His
last two months of life were characterized by a progressive downhill course with
congestive heart failure, marked personality changes, slurring of speech, ptosis of
the left upper lid, increasing weakness, and enlargement of the liver and spleen.
The day prior to death he had an extension of the previous myocardial infarct, and
he exhibited ventricular brillation at death the following day. During the last two
months of life, he was treated with amphotericin B via a nasogastric tube and an
experimental antifungal drug (RO–2), without apparent benet.
AUTOPSY FINDINGS
Necropsy was started 15 hours after death. See Figures 1A–1D. Effusions were
present in the abdominal cavity (925 milliliters), pleural spaces (420 and 150
milliliters), and pericardial sac (70 milliliters). The heart weighed 400 grams. The
right and left atria, tricuspid and mitral valves, right ventricle, and pulmonic valve
were unremarkable. There was aneurysmal dilatation of an infarct, 5 by 3.5 by 0.2
centimeters, in the anterior wall of the left ventricle. The left anterior descending
coronary artery was totally occluded just proximal to the myocardial infarct. Asoft,
friable, greyish vegetation was present on the ventricular aspect of each of the three
cusps of the aortic valve (Figures1A and 1B). The largest vegetation measured 2
centimeters in longest diameter.
The kidneys (Figure 2A) were enlarged; the left weighed 190 grams, and the
right, 180 grams. The surface of each kidney was glistening, greyish purple, and
smooth, except for two focal indentations in the right kidney. No petechiae were
noted on the surfaces. On section, the corticomedullary junctions were well
delineated. The ureters were widely patent. The large renal arteries and veins were
free of atheromata and of emboli.
The spleen weighed 1,000 grams and contained several infarcts. The liver
weighed 3,650 grams and, on section, had a nutmeg appearance. There was marked
generalized lymphadenopathy. The left internal iliac and left femoral arteries were
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Figure 1A Aortic valve viewed from above. The large vegetations almost totally
occlude the aortic valve orice.
Figure 1B Aortic valve opened. Note the presence of a vegetation on the ventricular aspect of each of the cusps of the aortic valve.
occluded by soft yellow emboli. Cultures were taken of the aortic valve vegetation,
spleen, liver, hilar lymph node, and left femoral artery and all grew C. parapsilosis.
Microscopically, Candida organisms were identied in the aortic valve
vegetations, left anterior descending coronary artery, myocardial infarct, left
femoral artery, and brain. The vegetations consisted of eosinophilic and basophilic
debris, brous tissue, and large colonies of Candida organisms (Figures1C and 1D).
The left anterior descending coronary artery was totally occluded except for a small
organizing channel which contained Candida organisms. Sections of the myocardial
infarct disclosed that the myocardial bers were largely replaced by brous tissue,
which contained macrophages, lymphocytes, plasma cells, broblasts, Langhans
type giant cells, and a few Candida organisms.
In the sections from the kidneys, there were focal areas of brinoid necrosis
and brosis in numerous glomeruli (Figures2B–2D). Some of the glomeruli were
completely hyalinized. Approximately 90% of the glomeruli were involved in some
manner by the brinous and brous processes. No abnormalities were noted in the
uninvolved glomeruli or in the uninvolved portions of the affected glomeruli. The
diseased portions of the glomeruli were frequently adherent to Bowman’s capsule.
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Figure 1C Photomicrograph of section through the largest vegetation illustrated
in Figure 1B. The darker areas in the vegetation represent collections of Candida
organisms. Note that the sinus of Valsalva is free of vegetation. Gomori’s methenamine silver stain, × 10.
Figure 1D Photomicrograph (high power) of candida organisms present in vegetation shown in Figure1C. Gomori’s methenamine silver, × 495.
Figure 2A Surface of cut section of each kidney, showing marked congestion.
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Figure 2B Photomicrograph of kidney showing focal glomerular lesion which is
adherent to Bowman’s capsule. Hematoxylin and eosin stain, × 310.
Figure 2C Photomicrograph of renal glomerulus demonstrating “focal embolic
glomerulonephritis.” Some malpighian tufts are hyalinized; other tufts are normal.
Periodic acid-Schiff stain, × 310.
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Figure 2D Photomicrograph of glomerulus. Periodic acid-Schiff stain, × 415.
There was no cellular proliferation in the glomerular tufts. Proliferation of the
epithelium of Bowman’s capsule, however, to form epithelial crescents, occasionally
was seen. The basement membrane of involved glomeruli was usually thickened. In
some places, it was thickened in the absence of involvement of the glomerular tufts.
Heidenhain’s azan modication of Mallory’s connective tissue stain disclosed that
most of the focal glomerular lesions were of the “healed brous” type as described
by Bell.
9, 10
The “fresh hyalin” lesion of Bell was seen only occasionally, and then
frequently was associated with a “healed brous” lesion in the same glomerulus.
Red blood cells were present to a limited extent in Bowman’s space and commonly
were seen in the lumen of the tubules. The tubules immediately adjacent to some of
the more severely involved glomeruli were atrophic. Prussian blue stain revealed
the presence of iron pigment in numerous tubular cells, and in the lumina of some
tubules. Hyaline and granular casts also were present in the lumina of many tubules.
The interstitial tissue contained many focal collections of lymphocytes and plasma
cells. No fungi or bacteria were identied in the sections from the kidneys.
COMMENT
“Focal embolic glomerulonephritis” at one time was considered to be associated
only with subacute streptococcal endocarditis.
endocarditis produced by a number of other bacteria.
glomerulonephritis” has been reported in septicemia without endocarditis,
in rheumatic endocarditis,
six weeks’ duration—,
renal biopsy has disclosed the presence of focal glomerular lesions in a group of
patients who heretofore would not have been suspected of having this disorder.
Bates, Jennings, and Earle
of ten patients with proteinuria, hematuria, and pharyngitis, without bacterial or
immunological evidence of a recent hemolytic streptococcal infection. Heptinstall
6
11, 12
Subsequently, it was seen in
13
Furthermore, “focal embolic
9
in acute bacterial endocarditis—that is, of less than
9
and in systemic lupus erythematosus.
17
found focal glomerular lesions on renal biopsy in four
15, 16
The use of the
9, 14
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and Joekes
16
reported “focal glomerulonephritis” in 13 of 100 patients from whom
renal biopsies were obtained because of some urinary abnormality (usually
proteinuria and hematuria). Four of the patients were believed to have systemic
lupus erythematosus or polyarteritis nodosa, three appeared to have SchönleinHenoch purpura, and the remainder would have been diagnosed clinically as
having Ellis type II glomerulonephritis had the renal biopsies not been done.
The cause of “focal embolic glomerulonephritis” has not been denitely
determined. Löhlein,
to the embolization of minute fragments from the vegetations on the heart valves.
However, there are several reasons, which Allen
18
Baehr,
11,12
Fahr,14 and Bell9 ascribed the glomerular lesions
1
has summarized, to doubt this
concept. First, bacteria rarely are seen in the involved glomeruli. Second, focal
glomerular lesions are rarely found in acute endocarditis, which has even more
friable vegetations than does the subacute variety. Third, focal glomerular lesions
are seen, although rarely, in the presence of bacteremia alone, without endocarditis,
and in certain collagen diseases. In addition, “focal embolic glomerulonephritis” has
been seen with endocarditis that involved only valves on the right side of the heart.
19
Fourth, it is difcult to accept the idea that hundreds of approximately equal-sized
minute emboli are dislodged from a vegetation and seed only one organ, the kidneys,
practically to the exclusion of others. Fifth, “focal embolic glomerulonephritis”
cannot be produced experimentally by injecting solid particles into the blood
stream of an animal. Thus, since these focal glomerular lesions do not appear to
result from the implantation of minute emboli in the glomerular capillaries, since
they occur in the absence of endocarditis, as well as in its presence, and since there
usually is no inammatory response in the glomeruli, the terms “embolic,” “endocarditic,” and “-nephritic” should be discarded. We favor, as does Fishberg,
the descriptive term, “focal glomerular lesions.” (As pointed out by Heptinstall and
16
Joekes,
the glomerular lesions are local as well as focal. The “local” refers to the
13
simply
condition in which only a part of an individual glomerulus is involved by the lesion
and the “focal,” to the condition in which some glomeruli are involved and others
are uninvolved, the latter being normal.)
Since the embolic mechanism seems untenable, the immuno-allergic theory has
found much favor. Originally suggested by Longcope
2
and advanced later by Allen,1
this idea ascribes the glomerular lesion to sensitization of the glomerular capillaries,
to the bacteria themselves, or to the products of the bacteria present in the blood. This
hypothesis is consistent with the occurrence of “focal embolic glomerulonephritis”
in occasional cases of acute bacterial endocarditis, in bacteremias without
endocarditis, and in isolated right-sided endocarditis. Since it is known that
Candida organisms are good antigens, the immuno-allergic theory also is consistent
with the occurrence of “focal embolic glomerulonephritis” in Candida endocarditis.
20
Drake
has shown that 45% of normal human sera agglutinate C. albicans, and that
approximately 40 or 50% of adults show a positive skin test to vaccine of C. albicans.
It seems reasonable to believe that the same mechanisms which produce “focal
embolic glomerulonephritis” in bacterial endocarditis also may play a role in the
focal glomerulonephritis associated with Candida endocarditis.
Of the 44 cases reported of endocarditis caused by the higher fungi and
proven at autopsy, 23 were due to Candida species.
3,21,22
The endocarditis in each
of the four patients with well-documented “focal embolic glomerulonephritis”
was caused by organisms of the Candida species. No focal glomerular lesions have
been reported in patients with endocarditis due to Coccidioides immitis, Cryptococcus
neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Aspergillus, or Mucor,
although several of these fungi appear to be good antigens. “Focal embolic
glomerulonephritis” has been mentioned in the protocols of three other patients
22–24
who died of endocarditis due to fungi, probably of Candida species, but these cases
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are omitted from this report because of inadequate diagnostic information. None
of the four patients with “focal embolic glomerulonephritis” listed in Table 1 had
an associated bacterial endocarditis. The patient reported by Kushner and Szanto,
21
with “focal embolic glomerulonephritis” associated with fungal endocarditis,
also had bacteria in the cardiac vegetations and is therefore excluded from this
report. The incidence of “focal embolic glomerulonephritis” associated with fungal
endocarditis may be less than 10%, whereas the incidence of focal glomerulonephritis
associated with subacute bacterial endocarditis is in the order of 50 to 90%.
9–11
There
was no mention of organs other than the heart in several reports of patients with
fungal endocarditis; consequently, the former percentage is probably low. Diffuse
glomerulonephritis is uncommon in bacterial endocarditis and has not been
mentioned in any reports of patients with fungal endocarditis.
Table 1 summarizes the renal ndings in the documented cases of “focal
embolic glomerulonephritis” associated with fungal endocarditis. Examination
of the urinary sediment is of little help in distinguishing “focal embolic
glomerulonephritis” from diffuse glomerulonephritis. Although the hematuria
associated with focal glomerular lesions is classically microscopic and transient,
massive, though intermittent, hematuria does occur (patient 2, Table1). Leukocytes
were described in the urinary sediment of two patients, but pyelonephritis was
present histologically in all four patients (Table 1) at autopsy. Bacteria rarely are
present in the glomeruli of patients with focal glomerular lesions associated with
subacute endocarditis due to bacteria. In contrast, fungi were seen in the kidneys
in two of the four patients with “focal embolic glomerulonephritis” associated
Table 1: Patients with focal glomerular lesions (focal embolic glomerulone phritis)
in fungal endocarditis
Patients 1 2 3 4
Author Pasternack Neil-Kohlmeier Neil-Kohlmeier Present Author
Year 1942 1953 1953 1962
Age (years), sex 45M 41M 60 F 26M
Length of illness
(months) 1¼ 3 2 11
Location of
endocarditis
(heart valve) Aortic Aortic Mitral Aortic Mitral Aortic
Organism causing
endocarditis C. parapsilosis C. albicans C. guilliermondi C. parapsilosis
Renal function
Specic gravity 1.018 1.027 1.010
Pyuria 0 + +
Hematuria + 0 +
Cylindruria + + +
Uremia + +
Renal morphology
Pyelonephritis + + + +
Infarcts + 0 0 0
Size ↑ Normal Normal ↑
“Flea-bitten”
surface
(petechiae) 0 + 0 0
No. of glomeruli
involved “Occasional” “Severe” “Slight” 90%
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with endocarditis due to fungi. The fungi were present in the glomeruli as well
as in the lumina of the tubules and in the interstitial tissues. In each of the two
patients with C. tropicalis without endocarditis reported by Richart and Dammin,
25
Candida organisms were present in the glomeruli, as well as intratubularly and
interstitially. In addition, in one of their patients, there was “partial destruction
of the glomerular tuft without inammatory response.” The latter nding may
represent an example of “focal embolic glomerulonephritis” associated with
candidiasis without endocarditis.
Uremia was present in two of the four patients with focal glomerular lesions
associated with fungal endocarditis (Table1). Uremia on the basis of “focal embolic
glomerulonephritis” associated with subacute bacterial endocarditis has been
considered a rarity. Indeed, Libman is quoted by Fishberg
cases of subacute bacterial endocarditis he never had seen uremia due to focal
glomerular lesions. Boyarsky, Burnett, and Barker,
literature of 16 patients with “focal embolic glomerulonephritis” that produced
uremia, and they added one of their own. Baehr
26
11
felt that renal function was rarely
13
as saying that in 800
however, found reports in the
altered in the presence of focal glomerular lesions because the uninvolved portions
of the damaged glomeruli remained normal, leaving enough healthy glomerular
tissue to maintain normal glomerular functions.
SUMMARY
“Focal embolic glomerulonephritis” may occur in patients with endocarditis due
to organisms other than bacteria, and indeed may occur occasionally in patients
without endocarditis. Ayoung man is presented who had endocarditis due to a
fungus (Candida parapsilosis) and whose kidneys at autopsy showed the classical
lesion of “focal embolic glomerulonephritis.” It is mentioned that “focal embolic
glomerulonephritis” probably occurs, proportionally, less commonly in fungal
than in bacterial endocarditis. This lesion has been described in only four of 44
autopsied patients who died of fungal endocarditis, and in each of the four the
endocarditis was caused by organisms of the Candida species. The term “focal
embolic glomerulonephritis” is considered unsatisfactory, since the process appears
not to be “embolic,” and there rarely is an inammatory response in the glomeruli.
The descriptive term “focal glomerular lesions” is preferred.
ACKNOWLEDGMENT
The authors wish to thank Doctors Arthur Allen and Paul Kimmelsteil for reviewing
the histological sections from the kidneys, and Doctors Louis B. Thomas and Ross C.
MacCardle for reviewing the manuscript.
SUMMARIO IN INTERLINGUA
“Focal glomerulonephritis embolic” pote occurrer in patientes con endocarditis
causate per organismos altere que bacterios; de facto, illo pote occurrer in patientes
qui ha nulle endocarditis del toto. Es presentate le caso de un juvene homine qui
habeva endocarditis causate per un fungo (Candida parapsilosis) e in qui le renes
revelava al necropsia le lesion classic de “focal glomerulonephritis embolic.” Es
mentionate que “focal glomerulonephritis embolic” occurre probabilemente in un
plus basse procentage del casos in endocarditis fungal que in endocarditis bacterial.
Iste lesion esseva notate in solmente quatro de 44 necropsiate patientes morte ab
endocarditis fungal, e in omne ille quatro casos le endocarditis esseva causate per
organismos del specie Candida. Le termino “focal glomerulonephritis embolic” es
considerate como non satisfactori in vista del facto que le processo non pare esser
embolic e que il occurre rarmente un responsa inammatori in le glomerulos. Le
termino descriptive “focal lesiones glomerular” es preferite.
9
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