Acute Eosinophilic Interstitial Nephritis and Renal
Failure with Bone Marrow-Lymph
and Anterior Uveitis
A New Syndrome
ROBERT S. DOBRIN, M.D.”
ROBERT L. VERNIER, M.D.
ALFRED J. FISH. M.D.+
Minneapolis, Minnesota
From the Department of Pediatrics, Division of
Pediatric Nephrology, University of Minnesota,
Minneapolis, Minnesota. This study was sup-
ported by Grants Al 10704 and HL 06314 from
the National Institutes of Health, Bethesda,
Maryland. Requests for reprints should be ad-
dressed to Dr. Alfred J. Fish, University of Min-
nesota Medical School, Division of Pediatric
Nephrology. Box 491, 13th Floor, Health Sci-
ences Unit A, Minneapolis, Minnesota 55455.
Manuscript accepted November 1, 1974.
l Present address: Box 271, The Rockefeller
University, 66th Street and York Avenue, New
York, New York 10021.
+ Established Investigator, American Heart
Association.
Node Granulomas
We describe two patlents with a unique granulomatous syndrome
who presented with renal failure secondary to diffuse eosinophilic
interstitial nephritis. Both had bilateral anterior uveltis, bone mar-
row granukmas, hypergammagkbulinemia and an increased
sedimentatlon rate. One patient had lymph node granukmas and
an immunoglobulln G (IgG) rheumatoid factor. An extensive in-
vestigation for an etkkgic agent was unrewarding, and neither
patient could be placed into any existing diagnostic category.
Over a period of 2 years both patients have experienced im-
proved renal function and dissolution of their bone marrow granu-
lomas
Eosinophilic interstitial nephritis, lymph node-bone marrow granulo-
mas and anterior uveitis have been described in association with a
variety of syndromes. Acute eosinophilic nephritis has been linked
to drug-induced hypersensitivity reactions [ 11. Granulomatous dis-
eases and uveitis have occurred with infections, disorders of immu-
nity and systemic syndromes of unknown etiology [2,3]. We de-
scribe two patients who had the unique triad of acute eosinophilic
interstitial nephritis with renal failure, bone marrow-lymph node
granulomas and bilateral anterior uveitis. An exhaustive investiga-
tion failed to reveal either an infectious agent or a nephrotoxin. One
patient was treated with systemic steroids for 10 l/2 months; both
have recovered from this disease.
MATERIALS AND METHODS
Technics of renal biopsy, light histology, immunopathology and electron
microscopy have been cited elsewhere [4.5]. Double diffusion analysis
was carried out by the method of Ouchterlony [6]. Immunoelectropho-
resis was performed by the method of Scheidigger [7]. lmmunoglobulins
were quantitated using Meloy standard immunodiffusion plates in accor-
dance with the method of Mancini et al. [8]. Latex fixation assay for rheu-
matoid factor was carried out utilizing the method of Singer and Plotz [9].
Characterization of the rheumatoid factor and cryoglobulin determinations
September 1975 The American Journal of Medicine Volume 59 325
RENAL FAILURE AND INTERSTITIAL NEPHRITIS-DOBRIN ET AL

ceding history of rash, ingestion of toxins, drug abuse,

dysuria, frequency, cough or fever. Her family doctor had
prescribed sulfasoxazole (Gantrisine), 500 mg four times a
day, during 1 week in early December. At that time urinaly-
sis showed proteinuria, pyuria and cylinduria. An intrave-
nous pyelogram revealed enlarged kidneys. All antibody
studies and a throat culture were negative for streptococ-
Cal infection. Because of persistent symptoms associated
with pallor, weight loss, nocturia and laboratory evidence
of worsening renal function (blood urea nitrogen 46 mg/
100 ml, creatinine 2.0 mg/lOO ml), she was referred to
the University of Minnesota Hospitals in late December.
The family history was unremarkable for any type of renal
disease or related syndrome.
On admission, physical examination revealed a tall,
pale, asthenic preadolescent with no apparent edema. Her
blood pressure was 110 to 120170 mm Hg; her respiratory
Figure 1. Case 7. The first renal biopsy specimen. Pho- rate was normal. There was no evidence of peripheral ad-
tomlcrograph of an hematoxylin-eosin stained tissue dem-
enopathy or hepatosplenomegaly. She had bilateral flank
onstrating diffuse interstitial infiltrate with round cells and
pain to percussion.
eosinophils. No granulomas are seen. Glomeruli are within
Initial laboratory studies yielded the following results: he-
normal limits. Original magnification X 290, reduced by 70
matocrit 30 per cent, hemoglobin 10.8 g/100 ml, white
per cent.
blood cell count 10,850/mm3 with a normal differential,
erythrocyte sedimentation rate 108 mm, creatinine 5.0
were performed by Dr. Erskine Caper-ton, University of mg/iOO ml, blood urea nitrogen 70 mg/lOO ml, creatinine
Minnesota, by previously described methods [ 10.1 I], and clearance 14 cc/min/1.73 m*; the serum calcium, phos-
total hemolytic complement was quantitated by Drs. phorus, alkaline phosphatase, antistreptolysin 0 titer
McLean and Michael [ 121 as described elsewhere. Immu- (ASO) and ornithine carbamyl transferase were normal. A
noglobulin E (IgE) was determined by a radioimmunoassay mononucleosis spot test was negative. Other laboratory
technic [ 131. HL-A typing was carried out in the laboratory data included an elevated IgG level of 2,500 mg/ 100 ml
of Dr. Edmund Yunis, University of Minnesota [ 141. Nicker- and a normal IgE level of 137.0 ng/ml (normal limits 6 to
son-Kveim antigen was kindly supplied by Dr. Laurence
Siltzbach [ 151. Viral culture studies were performed by Dr.
Henry Balfour, State Health Department Laboratories, Min-
neapolis, Minnesota. Bacterial and fungal cultures were
made in the Microbiology Laboratory, University of Minne-
sota Hospitals. Cold agglutinins, febrile agglutinins and
Australia antigen titers were determined at the laboratories
of the University of Minnesota Hospitals. Tissue target fluo-
rescent antinuclear antibody was determined on mouse
liver in the laboratory of Dr. Alfred Michael, Department of
Pediatrics, University of Minnesota. Complement fixation
studies for various pathogens were evaluated at the Com-
municable Disease Center, Atlanta, Georgia. Complement
fixation studies for four strains of leptospirosis were car-
ried out at the University of Minnesota School of Veterina-
ry Medicine, St. Paul, Minnesota. T cell response to vari-
ous mitogens was evaluated by Dr. DuPont [ 161. Nitroblue
tetrazolium reduction was carried out according to the
method of Park et al. [ 171. Serum and urine creatinine lev-
els were determined according to an automated modifica-
tion [ 181 of the method of Jaffee.

CASE REPORTS
Case 1. A 14 year old white girl was referred to the Uni-
versity of Minnesota Hospitals because of renal insufficien-
cy. She was well until late November 1971 when she ex-
perienced bilateral flank pain, intermittent abdominal
cramps, nausea, anorexia and malaise. She had no pre-
Figure 2. Case 1. The first bone marrow biopsy speci-
men. This hematoxylin-eosin particle crush preparation re-
veals a representative granuloma without a multinuclear
giant cell. The epithelioid cells have abundant eosinophilic
cytoplasm. The cells surrounding the granuloma consist of
small lymphocytes. Original magnification X 280, reduced
by 10 per cent.

326 September 1975 The American Journal of Medlclne Volume 59


60-
::
SN
b & 50-
$h
by
uh-
:S F
$ :: 30-
d
20-
IO-
Figure 3. Case 1. The clinical course. o---o
The relationship between renal function, Uvri?is.
red blood cell sedimentation rate and DEC
1971
uveitis.
540 ng/ml). Total hemolytic complement and the third
component of complement (C3) were normal; rheumatoid
factor and fluorescent antinuclear antibody screen were
negative. Skeletal and chest films were within normal lim-
its.
A percutaneous renal biopsy specimen revealed a dif-
fuse interstitial nephritis composed of leukocytes, which
were predominantly eosinophils and some plasma cells,
and lymphocytes. The glomeruli were normal, but there
were focal areas of tubular necrosis. There was no evi-
dence of vascular injury, and granulomas were not found
(Figure 1). Cultures of the renal biopsy specimen were
negative for bacteria, virus and fungi. The immunopatholo-
gic analysis of this biopsy specimen was negative for lo-
calization of immunoglobulins, including IgE and comple-
ment components. Many autofluorescent granulocytic
cells were noted in the interstitium.
Bone marrow examination revealed one giant cell in the
smear and two small granulomatous lesions in the trephine
biopsy preparation (Figure 2). The smears also demon-
strated markedly increased iron stores and macrophages
containing heavy concentrations of stainable iron. Immu-
nofluorescence studies of the bone marrow for localization
of immunoglobulins were negative as were all bacterial,
viral and fungal cultures.
The hospitalization was marked by the patient’s continu-
ing clinical improvement without specific treatment (Figure
3). This was paralleled by a decline in erythrocyte sedi-
mentation rate, and levels of blood urea nitrogen and
serum creatinine, to 26 mg/lOO ml and 1.9 mg/lOO ml, re-
spectively. All cultures of the patient’s blood, throat, urine
and stool, including those for brucellosis, leptospirosis and
tuberculosis were negative repeatedly. Antibody studies
for herpes simplex virus, Australia antigen, toxoplasmosis,
cytomegalovirus and El3 virus were negative as were titers
September 1975
RENAL FAILURE AND INTERSTlTlAL NEPHRITIS-DORRIN ET AL.
1,
+ II
+ I I I
’ JAN ” MAR ” AUG ‘( DEC ” JUL
1972 1973
for Australia antigen. Cold agglutinins and febrile agglutin-
ins were normal. Serologic studies for fungi (histoplasmo-
sis, coccidiomycosis, blastomycosis and cryptococcosis)
were within normal limits. A screen for urinary toxins and
heavy metals was also within normal limits.
A second renal biopsy specimen, obtained 1 month
later, showed an interstitial infiltrate characterized by mo-
nonuclear cells. There was a diffuse increase in interstitial
fibrous tissue, no evidence of calcium deposits and no
granulomas. The glomeruli were normal. The findings on
immunopathologic examination of this biopsy specimen
were similar to the first study but showed fewer autofluo-
rescent cells.
Ten weeks after discharge (March 1972) the patient ex-
perienced blurring of vision, conjunctival erythema and ex-
cessive tearing assooiated with submandibular swelling
and pain. Ophthalmologic examination revealed conjuncti-
vitis, but no irregularity of the iris. Slit lamp evaluation re-
vealed an anterior uveitis with fine keratotic precipitates.
Treatment consisted of atropine and a topical steroid. The
uveitis responded to local therapy and subsided. A repeat
bone marrow biopsy revealed no granulomas and a skin
biopsy of the Kveim reaction site was negative for granu-
loma formation (Figure 3).
Skin tests performed in May 1972, when renal function
was approaching normal, revealed no reaction to atypical
Mycobacteria, Candida albicans, histoplasmosis and coc-
cidiomycosis antigens; however a skin test with streptoki-
nase-streptodornase (sk/sd) was positive. Serial nitroblue
tetrazolium tests were normal. Repeat studies for rheuma-
toid factor were also negative. Tables I and II summarize
the clinical and laboratory features in Case 1.
Case 2. In January 1972, this 17 year old white girl had
an insidious onset of malaise, anorexia, low grade noctur-
The American Journal of Medlclne Volume 59 327
RENAL FAILURE AND INTERSTITIAL NEPHRITIS-DOBRIN ET AL

TABLE I Syndrome Analysis: Historic Evaluation

Case 1 Case 2

Presentation Malaise, anorexia, Malaise, anorexia,

flank pain, weight weight loss, fever,
loss, pallor, noc- flank pain, noc-
turia, no fever, renal turia, renal failure
failure
Past medical No allergic history, no Allergic history, no
history hospitalizations hospitalizations
Preceding Gantrisin@ for 1 wk;* Erythromycin for 1
drugs ampicillin for 1 wk.* wk;* rhondomycin
for 1 wk.*
Abnormal Not done Yes
urinalysis
prior to
antibiotic
therapy
Rash None None
Joint com- None None
plaints Case 2. First renal biopsy specimen. Photomi-
Figure 4.
*These drugs were not outdated. crograph of a hematoxylin-eosin stained preparation dem-
onstrates the severe interstitial infiltrate. The glomerulus is
relatively normal. Original magnification X 230, reduced
TABLE II Syndrome Analysis: Laboratory Evaluation
by 10 per cent. Insert: an accumulation of eosinophils (ar-
Case 1 Case 2 rows) adjacent to a tubule. Original magnification X 580,
reduced by 10 per cent.
Interstitial Predominantly Predominantly
nephritis eosinophilic eosinophilic
Granulomas Bone marrow Bone marrow
(noncaseating) lymph node
Uveitis Symptomatic, Asymptomatic,
anterior anterior
uveitis with nongranu-
Pk deposits lomatous
Eosinophilia Absent Intermittent
Kveim reaction Negative Not done
Increased stainable Present Present
iron in bone marrow

Renal function

Serum creatinine 5.0-3.2 8.2-4.8

(mg/lOO ml) and
creatinine clearance 14-26 8-20
(cc/min/1.73 mz)
during initial
hospitalization
Quantitative protein 0.2-0.9 0.2-0.7
excretion (g/24 hr)

Serologic evaluation

Quantitative IgG 2,500 2,200

(normal 520-1,800
mg/lOO ml)
Quantitative IgE 137.0 1,580-3,000
(normal 6-540 ng/ml)
Figure 5. Case 2. First bone marrow biopsy specimen.
IgG rheumatoid factor Negative 1:2,560-1:5,120
Photomicrograph of a hematoxylln-eosin stained prepara-
Sedimentation rate 108-70 124-66
tion demonstrates a typical noncaseating granuloma with
(Westergren mm/hr)
large, acidophillc epithelioid cells. Surrounding lympho-
during initial
cytes are abundant. Original magnification X 280, reduced
hospitalization
by 10 per cent. insert: representative multinuclear giant
Total complement Normal Normal
cell also found in this biopsy specimen. Original magnifica-
BlC/BlA Normal Normal
tion X 640, reduced by 10 per cent.

328 September 1975 The American Journal of Medicine Volume 59

 RENAL FAILURE AND INTERSTITIAL NEPHRITIS-DOBRIN ET AL.

nal fevers associated with chills and a 30 pound weight TABLE III Diagnostic Workup of Bone Marrow and
loss. When first examined because of complaints of phar- Lymph Node Granulomas Associated with
yngitis and fever, approximately 6 weeks later, the white Uveitis and Eosinophilic Interstitial Nephritis
--_---.-
blood cell count was 19,000/mm3 (predominantly polymor-
Differential Diagnosis of
phonuclear cells, with no increase in number of eosino- Bone Marrow Granulomas Tests Excluding the Diagnosis
phils); a throat culture and a urinalysis were negative. The
patient was treated with erythromycin (250 mg four times Malignant lymphoma No neopfastic cells found in tis-
a day) for 1 week without improvement followed by meth- sue analysis of bone marrow or
acycline hydrochloride (Rhondomycine), 600 mg/day, with lymph node. Negative bone
little benefit. Physical examination, chest films, urine cul- survey. No hepatosplenome-
galy. Atypical renal biopsy.
ture, skin tests for histoplasmosis and tuberculosis were
Tuberculosis Negative skin test, stains, cul-
all within limits. A repeat urinalysis in March showed pro-
tures. Negative chest films.
teinuria and microscopic hematuria, her blood urea nitro-
Atypical renal biopsy.
gen was 42 mg/ 100 ml, and she was hospitalized.
Sarcoidosis Negative chest films, normal pul-
Physical examination revealed exogenous obesity and
monary function, normal bone
normal blood pressure. Laboratory data included a white survey, negative Kveim test,
blood cell count of 12,700/mm3 with 74 per cent polymor- atypical course and renal
phonuclear cells and 4 per cent eosinophils; a hemoglobin biopsy, normal serum calcium.
level of 11.3 g, serum creatinine of 4.2 mg/lOO ml, creati- Granulomatous hepatitis Normal liver function.
nine clearance of 11 cc/min/l.73 m2 with 600 mg of urine Histoplasmosis Negative chest films, negative
protein/24 hours, erythrocyte sedimentation rate of 105 culture, serology, stains.
mm, a negative heterophil test, a nonreactive serologic Infectious mononucleosis No atypical lymphocytes, nega-
test for syphilis, an antistreptolysin 0 tier of 50 Todd units, tive serology, negative EB viral
and a negative culture and serology for cryptococcosis, titer, atypical course.
tuberculosis and histoplasmosis. Serum uric acid and cal- Brucellosis Negative serology and culture.
cium were normal. Urine cultures were sterile and an intra- Sjogren’s syndrome and Very atypical presentation. No
venous pyelogram showed large normally shaped kidneys. Mikulicz’sdisease physical signs; a normal paro-
Because of a progressive rise in serum creatinine to 6.6 (with uveitis) tid gland.
mg/lOO mg, a surgical renal biopsy was performed. The Collagen-vascular Normal total hemolytic comple-
kidney appeared to be pale and somewhat granular. Mi- disorder ment and C3, negative anti-
croscopic examination of tissue sections revealed an in- DNA and antinucteolar anti-
bodies; negative lupus erythe-
tense interstitial inflammatory process in which the pre-
matosus clot test and immuno-
dominant cells were eosinophfls. with a lesser number of
pathology of kidney biopsy.
plasma cells and lymphocytes (figure 4). The patient was
Wegener’s No evidence of vasculitis or peri-
subsequently referred to the University of Minnesota Hos-
granulomatosis arteritis. No granulomatous in-
pitals in April 1972 because of deteriorating renal function,
volvementof the upperor lower
eosinophilic interstitial nephritis and blurred vision. Rele- respiratory tract. Atypical kid-
vant past medical history included asthma and childhood ney biopsy; no glomerulopathy.
eczema. There was no familial renal disease nor was -_._
there a history of exposure to toxins or drug abuse. The
review of systems was completely negative for cough, atosus, syphills and cryoglobulinemia were negative. The
sputum production, dry eyes, abnormalities of taste, rash, level of rheumatold factor was persistently elevated (1:
joint complaints or acholic stools. 2560) IgG was 2,120 mg/lOO ml and IgE was 1,580 ng/
The findings on physical examination were unchanged; ml.
there were no obvious abnormalities of her eyes, no The patient was anergic to a variety of skin test anti-
lymphadenopathy, rash, organomegaly or edema. Labora- gens including mumps, Candii albicans. histoplasmosis.
tory data on admission included a hematocrit of 27 per coccidiomycosis, blastomycosis, various atypical Myco-
cent, a hemoglobin of 9.1 g/100 ml, a whine blood cell bacteria and streptokinase/streptodornase.
count of 8,700 cells/mm3 with a normal differential and no Ophthalmologic evaluation revealed low grade bilateral
atypical lymphocytes. Subsequent white blood cell counts nongranulomatous uveitis. Bone marrow aspiration and bi-
ranged between 6 and 20,000 cells/mm3, with intermittent opsy revealed deflniie noncaseating granulomas and in-
eosinophilia (less than 10 per cent); erythrocyte sedimen- creased iron stores (Figure 5). Cultures and stains for tu-
tation rate was 125 mm, and urinalysis revealed protein- berculosis and atypical Mycobacteria, anaerobic and aero-
uria (0.6 to 0.8 g/24 hours), glucosuria and microscopic bic bacteria, fungi and helminths were negative. Viral cul-
hematuria. Other laboratory values were blood urea nitro- tures were also negative. Complement fixation studies for
gen 53 mg/lOO ml, serum creatinine 7.2 mg/lOO ml, cre- leptospirosis. histoplasmosis. brucellosis, toxoplasmosis
atinine clearance 8 cc/min/1.73 m2 and normal calcium, and cryptococcosis were negative. Additional studies da
serum glutamic oxaloacetic transaminase and alkaline signed to exclude diseases associated with bone marrow
phosphatase. Roentgenograms of hands, skull and chest granulomas were negative (Table Ill). Cultures of blood,
were within normal limits. Pulmonary function studies were urine, stool and throat were also negative. All acute and
also normal. Serologic studies for systemic lupus erythem- convalescent antibody titers for Australia antigen, toxo-

September 1975 The Amerfcan Journal of Yodkirte Vdume 59 329

 RENAL FAILURE AND INTERSTITIAL NEPHRITIS-DDBRIN ET AL.
Figure 6. Case 2. Lymph node biopsy specimen. Hema-
toxylin-eosin stained preparation demonstrates two we//
defined granulomas. The granuioma on the right contains
epithelioid cells with indefinite cytoplasmic borders where-
as the granuloma on the left contains both epitheltokl cells
and a multinucleated giant cell; each is surrounded by
small lymphocytes. Sections stained for acid-fast bacilli
and fungi were negative. Original magnification X 430, re-
duced by 10 per cent.
plasmosis, cytomegalovirus, herpes simplex, ECHO virus,
mumps and coxsackie virus were negative.
A biopsy specimen of a submandibular lymph node re-
vealed small cortical and medullary granulomas formed by
multinuclear (Langhan’s type) cells and epithelioid cells
(Figure 6). Acid-fast, fungal, viral and bacterial studies
were negative. A parotid gland biopsy specimen showed
no granulomas, and had normal appearing serous glands
with minimal periductal lymphocytic infiltration. Treatment
consisted of steroid eye drops and a modified Giovanetti
diet. A repeat percutaneous renal biopsy specimen re-
vealed histologically normal glomeruli, a severe degree of
tubular atrophy, interstitial fibrosis with mononuclear infil-
trate and edema (Figure 7). A small collection of epithelioid
cells associated with a multinucleated giant cell was noted
in one area.
T cell function studies revealed a normal response to
phytohemagglutinin and pokeweed mitogen, but no re-
RF rmr. I:2660 t2660
330 September 1975 The American Journalof Medklne
Figure 7. Case 2. Second renal biopsy specimen. Tissue
preparation stained with azocarmine demonstrating a
moderately severe degree of interstitial fibrosis, persistent
mononuclear infiltrate with a normal appearing glomerulus.
Original magnification X 350, reduced by IO per cent.
sponse to a purified protein derivative test for tuberculosis,
Escherichia coli, Staphylococcus aureus and a borderline
response to Candida. Treatment with daily systemic ste-
roids was begun in May 1972 (Figure 8). Over a period of
10 l/2 months the dose of steroids was gradually tapered
on an alternate day regimen. The uveitis was suppressed
with topical therapy until a flare in November 1973. This
exacerbation was not associated with decreased renal
function or increased rheumatoid factor. Since June 1972
renal function has gradually increased to near normal (106
cc/min/ 1.73 m*) whereas the erythrocyte sedimentation
rate has remained within normal limits. A repeat bone
marrow examination in June 1974 failed to reveal granulo-
mas; cultures were negative for viruses, anaerobic and
aerobic bacteria, tuberculosis, fungi and atypical Myco-
bacteria. The level of rheumatoid factor remains elevated
t640 cE.120
Figure 6. Case 2. Clinical course. The
relationship between renal function, red
blood cell sedimentation rate, uveitis,
rheumatoid factor and therapy.
Volume 59

at I:640 and the uveitis is under control with daily tOpicZrl
steroids. Figure 8 outlines the clinical course, and Tables I
and II summarize the clinical and laboratory features in
Case 2.
COMMENTS
We describe two adolescent girls with a unique gran-
ulomatous process associated with severe eosino-
philic interstitial nephritis and renal failure. Both pa-
tients had bone marrow granulomas and bilateral an-
terior uveitis whereas one also had lymph node gran-
ulomas.
Interstitial nephritis has been described in associa-
tion with various autoimmune related syndromes
[18-201, infections [ 2 l-231, drug reactions
[20,24-261 and toxins [22]. Among the infectious
agents associated with interstitial nephritis have been
streptoccocci, diphtheria, leptospirosis and brucell-
osis; whereas uric acid, calcium, lead, cadmium, ber-
ylium and fluoride have been implicated as toxic
causes of interstitial nephritis and fibrosis. Our inves-
tigation failed to reveal evidence in support of any of
these processes. Among the drugs that have been
recognized as possible causes of interstitial inflam-
mation of the kidney are methicillin, penicillin, fura-
dantin, sulfonamides, phenidione, phenacetin and
some diuretics [ 1,22,24-271. One type of clinical
syndrome associated with drug-induced renal disease
usually includes peripheral eosinophilia, rash, joint
complaints, chills, fever and a parenchymal kidney
infiltrate composed of mononuclear cells and eosino-
phils. A recent report suggests that high levels of
serum IgE may be associated with this type of inter-
stitial nephritis [28]. Another type of nephropathy,
i.e., analgesic nephropathy, usually follows prolonged
periods of treatment with large doses of the drug and
is thought to be related to excessive accumulation of
the agent [26,27].
The presentation, clinical course and laboratory
findings of the patients described are not typical for
drug-induced interstitial nephritis. Previous reports of
the syndrome did not include weight loss, polyuria,
flank pain, uveitis or granulomas. One patient (Case
1) did not have peripheral eosinophilia, rash or an el-
evated IgE level. The other patient (Case 2) had a
long history of allergy, yet her IgE level and her inter-
mittent peripheral eosinophilia did not reflect any
acute stimulus during this illness. She did not have
joint pain, rash or other stigmas usually associated
with a drug-related interstitial nephritis. In addition,
her urinalysis was abnormal prior to the administra-
tion of any antibiotics, and the total dose and duration
of antibiotic treatment were not similar to that re-
ported in drug-related syndromes [ 241.
Neither patient had any of the clinical or pathologic
September 1975
RENAL FAILURE AND INTERSTITIAL NEPHRITIS-DOERIN ET AL.
manifestations of infiltrative eosinophilic syndrome(s)
[29-311, Wegener’s granulomatosis [32] or allergic
granulomatosis [33,34]. In the latter syndrome, origi-
nally described by Churg and Strauss [34], the le-
sions were characterized by inflammatory exudate
rich in eosinophilic leukocytes, necrosis and severe
alterations of collagen with granulomatous (epithe-
lioid and giant cell) reaction. The clinical presentation
included asthma, fever, eosinophilia, leukocytosis,
anemia, recurrent pneumonitis, purpura and central
nervous system abnormalities; the disease was pro-
gressive, unremitting and almost indistinguishable
from periarteritis nodosa.
It is also unlikely that this syndrome is a variant of
sarcoidosis. In childhood sarcoidosis 83 to 100 per
cent of the patients have hilar adenopathy, 48 per
cent have a history of a cough, whereas up to 70 per
cent have hepatosplenomegaly and cervical adenop-
athy [35-371. Both of the patients we describe here
lacked adenopathy and hepatosplenomegaly during
2’/* years of observation. In two large series of child-
hood sarcoidosis in the United States, using the Nick-
erson-Kveim antigen, 16 of 18 patients and 19 of 23
patients, respectively, had positive Kveim reactions
[35,36]; our first patient had a negative Kveim reac-
tion using the same antigen preparation. Further-
more, there are no reports of childhood sarcoidosis
in which the initial presentation was acute renal in-
sufficiency secondary to eosinophilic interstitial ne-
phritis [35-401. In adult patients with sarcoidosis,
renal involvement is manifested by hypercalcemia
and nephrocalcinosis, nephrotic syndrome and mem-
branous and/or proliferative glomerulonephropathy,
renal insufficiency with vasculitis, and diffuse infiltra-
tive granulomas with interstitial nephritis [4 l-461.
Neither of our patients had the renal pathologic
changes discussed. Both patients experienced signif-
icant recovery of renal function, and repeat bone
marrow examination revealed dissolution of the gran-
ulomas; this clinical course has not been reported in
sarcoidosis [43-451.
Each patient underwent an extensive search for
other etiologies of bone marrow granulomas. The dif-
ferential diagnosis which guided this portion of the in-
vestigation was derived from the review of Pease
[2,47] and others [48-501. These studies are sum-
marized in Table Ill.
Uveitis is associated with a wide variety of system-
ic diseases, including those characterized by granulo-
mas [3,5 I]. This association may reflect alterations
in ocular vascular permeability induced by systemic
disease and “metastasis” of inflammatory stimuli to
the uvea [52]. Infections associated with anterior
uveitis include syphilis, tuberculosis, toxoplasmosis,
nematode infestation, cytomegalovirus and herpes
simplex virus infection [3,51,52]. The eyes are also
The American Journal of Medlcine Volume 59 331
RENAL FAILURE AND INTERSTITIAL NEPHRITIS-_DOBRIN ET AL.
frequently involved in sarcoidosis; lesions of the
globe include nummular keratitis, nodular scleritis and
granulomatous iritis with Koeppe nodules. The most
specific lesions associated with sarcoidosis are
snowball vitrous opacities [5 11. These lesions were
not seen in our patients. The fine precipitates seen in
the anterior chamber in our first patient (Case 1)
were considered to be granulomatous, but were not
diagnostic of any entity.
Other diseases associated with uveitis include Re-
iter’s and Behcet’s syndrome: but neither patient had
either the history or the physical findings compatible
with these syndromes. Reiter’s syndrome has been
linked to HLA-W27 [53]; our second patient (Case 2)
lacked this HLA locus.
The possible role of the eosinophil in the patho-
genesis of interstitial nephritis deserves consider-
ation. Our first patient (Case 1) did not have peripher-
al eosinophilia, a high serum IgE level or evidence for
deposition of IgE within the kidney. Our second pa-
tient (Case 2) had a long history of allergy and mild
eosinophilia (less than 10 per cent of the total white
blood cell count). No acute change in the eosinophil
count was noted during the illness, and there was
lack of IgE deposition within the renal interstitium.
Several stimuli can attract eosinophils in tissue in-
cluding histamine, antigen-antibody complexes, aller-
gens and peptides of fibrin [54-561. It is possible that
some antigenic insult within the renal parenchyma
stimulated an eosinophilic and mononuclear re-
sponse in both patients with concurrent activation of
lymphatic and bone marrow histiocytes resulting in
granuloma formation.
The efficacy of treatment with systemic steroids
cannot be adequately evaluated in this disorder, al-
though renal function improved rapidly after predni-
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ACKNOWLEDGMENT
We gratefully acknowledge the graphic assistance Of
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